Physiological Effects of Superoxide Dismutase on Altered Visual Function of Retinal Ganglion Cells in db/db Mice

Xiao, Changlai; He, Meihua; Ye, Nan; Zhang, Dongjuan; Chen, Baiyu; Guan, Youfei; Pu, Mingliang

doi:10.1371/journal.pone.0030343

Cited by 36 publications

(36 citation statements)

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“…This generation of superoxide by photoreceptors is not a side effect of using streptozotocin to induce diabetes, because staining for superoxide also has been found in photoreceptors of spontaneously diabetic animals (34). Because photoreceptors are the major cell type in the retina and possess more mitochondria than do other retinal cells, they are likely to be the major source of the retinal superoxide in diabetes.…”

Section: Discussionmentioning

confidence: 92%

Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Veenstra

Palczewski

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

287

285

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Accumulating evidence suggests that photoreceptor cells play a previously unappreciated role in the development of early stages of diabetic retinopathy, but the mechanism by which this occurs is not clear. Inhibition of oxidative stress is known to inhibit the vascular lesions of early diabetic retinopathy, and we investigated whether the diabetes-induced oxidative stress in the retina emanates from photoreceptors. Superoxide generation was assessed in retinas of male C57BL/6J mice made diabetic for 2 mo (4 mo of age when killed) using histochemical (dichlorofluorescein and dihydroethidine) and bioluminescence (lucigenin) methods. Photoreceptors were eliminated in vivo by genetic (opsin −/− ) and chemical (iodoacetic acid) techniques. Immunoblots were used to measure expression of intercellular adhesion molecule 1 and the inducible form of nitric oxide synthase. Diabetes increased the generation of superoxide by diabetic mouse retina more at night than during the day. Photoreceptors were the major source of reactive oxygen species in the retina, and their deletion (either genetically in opsin −/− mice or acutely with iodoacetic acid) inhibited the expected diabetes-induced increase in superoxide and inflammatory proteins in the remaining retina. Both mitochondria and NADPH oxidase contributed to the observed retinal superoxide generation, which could be inhibited in vivo with either methylene blue or apocynin. Photoreceptors are the major source of superoxide generated by retinas of diabetic mice. Pharmaceuticals targeting photoreceptor oxidative stress could offer a unique therapy for diabetic retinopathy.T he pathogenesis of diabetic retinopathy remains unclear, but prior work by us and others has provided strong evidence in animal models that oxidative stress and inflammatory processes play important roles in the development of the vascular lesions characteristic of early stages of this retinopathy (1, 2). Inhibition of oxidative stress by feeding antioxidants or overexpressing antioxidant enzymes has reduced diabetes-induced degeneration of retinal capillaries (3-7). Moreover, oxidative stress has been reported to regulate expression of proinflammatory proteins (8-10), which also have been shown to play a critical role in the pathogenesis of this early retinopathy (2). However, which cells of the retina are the major sources of such oxidative stress in diabetes is unclear. In vitro studies of retinal endothelial cells or Müller cells incubated in elevated levels of glucose have demonstrated that these cells can contribute to oxidative stress (11, 12), but the contribution of other cell types and their relative importance has not been studied.Rod and cone photoreceptor cells are the most prevalent cells in the retina. These postmitotic cells have a very high metabolic rate, using more oxygen than other cells throughout the body. They are also considered as likely contributors to the eventual development of retinal hypoxia and subsequent neovascularization in advanced stages of diabetic retinopathy (13,14). Th...

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Section: Discussionmentioning

confidence: 92%

Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Veenstra

Palczewski

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

287

285

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“…Incremental threshold luminance sensitivity tests were conducted according to previously published methods. 17,23 In general, a criterion response for threshold irradiance was obtained by gradually increasing the intensity levels of the testing stimuli; a firing rate of two spikes per second above the baseline rate was set as a threshold response. If none of the test stimuli produced exactly two spikes per second, the threshold was determined by linear interpolation.…”

Section: Physiological Recording and Data Analysismentioning

confidence: 99%

“…Recent results in our laboratory have shown that altered visual function in RGCs, characterized by reduced receptive field (RF) size, elevated luminance threshold, and attenuated contrast threshold, can be reversed by in vitro application of SOD. 17 However, SOD is an enzyme, which makes it difficult to use as a therapeutic agent. Tauroursodeoxycholic acid (TUDCA), a potent inhibitor of apoptosis, acts by interfering with the upstream mitochondrial pathway that leads to cell death, inhibiting oxygen radical production, reducing endoplasmic reticulum (ER) stress, and stabilizing the unfolded protein response.…”

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confidence: 99%

Effects of Tauroursodeoxycholic Acid and Alpha-Lipoic-Acid on the Visual Response Properties of Cat Retinal Ganglion Cells: An In Vitro Study

Xia

Huang

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Xia H, Nan Y, Huang X, Gao J, Pu M. Effects of tauroursodeoxycholic acid and alpha-lipoic-acid on the visual response properties of cat retinal ganglion cells: an in vitro study. Invest Ophthalmol Vis Sci. 2015;56:6638-6645. DOI:10.1167/iovs.15-17301 PURPOSE. To investigate the effects of tauroursodeoxycholic acid (TUDCA) and alpha-lipoicacid (ALA) on the visual response properties of cat retinal ganglion cells (RGCs) in wholemount retinas.METHODS. Young adult cats were divided into three groups: control, ALA, and TUDCA. In vitro single-unit extracellular recordings were performed on wholemount retinas to objectively evaluate the visual response properties of RGCs prior and post to antioxidant treatment. The visual responses properties of RGCs, including receptive field size, luminance threshold, and contrast sensitivity, were collected online and analyzed off-line with Axon Pclamp9. RESULTS.Most of the RF sizes were larger than those plotted prior to the 60 minutes dark adaptation. The luminance threshold was elevated in the control group (no treatment) but reduced post ALA treatment and significantly reduced post TUDCA treatment. The contrast threshold was significantly elevated in the control group (no treatment) and clearly elevated post ALA treatment but effectively sustained post TUCDA treatment. CONCLUSIONS.Retinal neurocircuitry deteriorates in wholemount retinas, resulting in abnormal visual response properties in RGCs. Alpha-lipoic-acid and TUDCA exerted beneficial neuroprotective effects by activating the antioxidant pathway, partially restoring the functionality of retinal neurocircuitry and significantly improving the visual response properties of RGCs. However, TUDCA appears to be more effective than ALA in reducing irradiance thresholds and improving contrast sensitivity.

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“…These altered visual functions could, at least partly, be due to oxidative stress (Xiao et al, 2012a). Therefore, the db/db mouse may represent an adequate model for studies on the pathogenesis of DR.…”

Section: P0880mentioning

confidence: 99%

“…The altered visual functions of RGCs were characterized by the reduced receptive field center size, elevated luminance response, and attenuated contrast gain in 12-and 20-week db/db mice, respectively. These altered visual functions could, at least partly, be due to oxidative stress (Xiao et al, 2012a). Therefore, the db/db mouse may represent an adequate model for studies on the pathogenesis of DR.…”

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confidence: 99%

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

Szabadfi

Pintér

Reglődi

et al. 2014

International Review of Cell and Molecular Biology

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Physiological Effects of Superoxide Dismutase on Altered Visual Function of Retinal Ganglion Cells in db/db Mice

Cited by 36 publications

References 51 publications

Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Effects of Tauroursodeoxycholic Acid and Alpha-Lipoic-Acid on the Visual Response Properties of Cat Retinal Ganglion Cells: An In Vitro Study

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

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