Blockade of neuronal nitric oxide synthase reduces cone cell death in a model of retinitis pigmentosa

Komeima, Keiichi; Usui, Shinichi; Shen, Jikui; Rogers, Brian S.; Campochiaro, Peter A.

doi:10.1016/j.freeradbiomed.2008.06.020

Cited by 69 publications

(66 citation statements)

References 40 publications

(58 reference statements)

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“…[47][48][49] Bax, Bcl-2, Calpain-2, and Caspase-3 are all critical factors in the photoreceptor apoptotic cascades. [50][51][52] Our study suggests that TES rectifies abnormalities in the apoptotic cascade by altering Bcl-2 and Bax expression, indicating that TES could be developed into a promising and general therapeutic strategy against multiple RP phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Topographic Quantification of the Transcorneal Electrical Stimulation (TES)–Induced Protective Effects on N-Methyl-N-Nitrosourea–Treated Retinas

Tao

Chen

Liu

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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METHODS. N-methyl-N-nitrosourea-administered mice received TES or sham stimulations and were subsequently subjected to electroretinography (ERG), multielectrode array (MEA), and histologic and immunohistochemistry examinations. Quantitative reverse transcriptionpolymerase chain reaction (qRT-PCR) analyses were also performed to determine the mRNA levels of Bax, Bcl-2, Calpain-2, Caspase-3, brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF). RESULTS.Amplitudes of ERG b-wave in the TES-treated mice were significantly larger than those in the sham controls (P < 0.01). Microelectrode array examination revealed that the photoreceptors in TES-treated retina were efficiently preserved (P < 0.01). Morphologic measurements showed that the central retina region was more consolidated than the other areas in the TES-treated mice. Together with the disproportionate distribution of immunostaining in retinal flat mounts, these findings indicated that different rescuing kinetics existed among regional photoreceptors. Compared with the sham controls, a significantly increased signal-to-noise ratio was also found in the TES-treated mice (TES100: 2.02 6 1.12; TES200: 4.42 6 1.51; sham: 0.25 6 0.13; P < 0.01). Moreover, qRT-PCR measurements suggested that the altered expression of several apoptotic factors and neurotrophic cytokines was correlated with TES-induced protection.CONCLUSIONS. Regional photoreceptors in the MNU-administered retinas exhibit different sensitivities to TES. Transcorneal electrical stimulation is capable of ameliorating MNUinduced photoreceptor degeneration and rectifying abnormalities in the inner visual signal pathways.Keywords: transcorneal electrical stimulation, therapeutic strategy, retinitis pigmentosa R etinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases characterized by initially impaired dark-adapted sight, progressive deterioration of visual fields, and eventual blindness. 1,2 Currently, the pathologic mechanisms of RP remain poorly understood, and there is no satisfactory therapeutic intervention.3 Retinitis pigmentosa models can be used to explore the pathologic mechanisms underlying this disorder, providing insights into the development of effective therapeutics. The N-methyl-N-nitrosourea (MNU) can pharmacologically induce photoreceptor degeneration. After a single systemic administration, active signs of retinal degeneration, such as decreased outer nuclear layer (ONL) thickness, degraded electroretinogram (ERG) response, and hyperexpressed apoptotic labeling, are indistinct in the MNU-treated retinas due to the selective photoreceptor cell loss. The mechanism underlying MNU-induced photoreceptor death is the principal alkylation of DNA, depending on the action of alkyladenine DNA glycosylase (Aag), an enzyme that removes alkylated bases via cleavage of glycosyl bond connecting base to the sugar phosphate backbone, thus generating abasic sites that can be further processed by the base excision repair machinery.4 N-methyl-N-nitrosourea ...

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Section: Discussionmentioning

confidence: 99%

Topographic Quantification of the Transcorneal Electrical Stimulation (TES)–Induced Protective Effects on N-Methyl-N-Nitrosourea–Treated Retinas

Tao

Chen

Liu

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…The primary cause of acute retinal degeneration after bright light exposure in Abca4 −/− Rdh8 −/− mice is the delayed clearance of atRAL from photoreceptors (18). Moreover, light-induced retinal degeneration in Abca4 −/− Rdh8 −/− mice can be prevented by pharmacological interventions such as the retinoid cycle inhibitor with a primary amino group, retinylamine (12,30), and the NAPDH oxidase inhibitor, apocynin (31,(47)(48)(49) (Fig. S3).…”

Section: Photoreceptor Cell Apoptosis Is Caused By Atral In Neural Rementioning

confidence: 99%

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

Maeda

Palczewska

Golczak³

et al. 2014

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

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Atrophic age-related and juvenile macular degeneration are especially devastating due to lack of an effective cure. Two retinal cell types, photoreceptor cells and the adjacent retinal pigmented epithelium (RPE), reportedly display the earliest pathological changes. Abca4 −/− Rdh8 −/− mice, which mimic many features of human retinal degeneration, allowed us to determine the sequence of light-induced events leading to retinal degeneration. Using two-photon microscopy with 3D reconstruction methodology, we observed an initial strong retinoid-derived fluorescence and expansion of Abca4 −/− Rdh8 −/− mouse rod cell outer segments accompanied by macrophage infiltration after brief exposure of the retina to bright light. Additionally, light-dependent fluorescent compounds produced in rod outer segments were not transferred to the RPE of mice genetically defective in RPE phagocytosis. Collectively, these findings suggest that for light-induced retinopathies in mice, rod photoreceptors are the primary site of toxic retinoid accumulation and degeneration, followed by secondary changes in the RPE.

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“…However, after the death of rods, the major consumers of oxygen in the retina, the tissue oxygen level in the outer retina is substantially increased [Yu et al, 2000] which activates NADPH oxidase and superoxide radicals accumulate [Usui et al, 2009b]. Superoxide radicals attack macromolecules causing oxidative damage and other molecules such as nitric oxide which generates peroxynitrite, a particularly damaging free radical that amplifies the damage [Komeima et al, 2008]. Over time the antioxidant defense systems and repair mechanisms in cones are overwhelmed leading to such severe cell damage that apoptosis is activated.…”

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confidence: 99%

N-acetylcysteine promotes long-term survival of cones in a model of retinitis pigmentosa

et al. 2011

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Retinitis pigmentosa (RP) is a major source of blindness caused by a large variety of mutations that lead to the death of rod photoreceptors. After rods die, cones gradually die from progressive oxidative damage. Several types of antioxidant formulations have been shown to reduce cone cell death over a relatively short-time frame, but in order for this strategy to be translated into a new treatment for patients with RP, prolonged effects will be needed. In this study, we determined that orally administered N-acetylcysteine (NAC) reduced cone cell death and preserved cone function by reducing oxidative damage in two models of RP, rd1(+/+) and rd10(+/+) mice. In rd10(+/+) mice, supplementation of drinking water with NAC promoted partial maintenance of cone structure and function for at least 6 months. Topical application of NAC to the cornea also reduced superoxide radicals in the retina and promoted survival and functioning of cones. Since oral and/or topical administration of NAC is feasible for long-term treatment in humans, and NAC has a good safety profile, it is reasonable to consider clinical trials to evaluate the effects of prolonged treatment with NAC in patients with RP.

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Blockade of neuronal nitric oxide synthase reduces cone cell death in a model of retinitis pigmentosa

Cited by 69 publications

References 40 publications

Topographic Quantification of the Transcorneal Electrical Stimulation (TES)–Induced Protective Effects on N-Methyl-N-Nitrosourea–Treated Retinas

Topographic Quantification of the Transcorneal Electrical Stimulation (TES)–Induced Protective Effects on N-Methyl-N-Nitrosourea–Treated Retinas

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

N-acetylcysteine promotes long-term survival of cones in a model of retinitis pigmentosa

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