Neuroprotection from Retinal Ischemia/Reperfusion Injury by NOX2 NADPH Oxidase Deletion

Yokota, Harumasa; Narayanan, S. Priya; Zhang, Wenbo; Liu, Hua; Rojas, Modesto; Xu, Zhimin; Lemtalsi, Tahira; Nagaoka, Taiji; Yoshida, Akitoshi; Brooks, Steven E.; Caldwell, Robert W.; Caldwell, Ruth B.

doi:10.1167/iovs.11-8318

Cited by 67 publications

(94 citation statements)

References 45 publications

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“…Genetic deletion of Nox2 also attenuated the intermittent hypoxiainduced cognitive deficits and markers of oxidative stress in mice (125). Finally, Nox2 deficiency reduced neuronal death, oxidative injury, and microglial activation in a model of murine transient global cerebral ischemia (183) and attenuated neuronal cell death within the ganglion cell layer in a mouse model of retinal I/R (182).…”

Section: Nox Homologs In Stroke: Nox2 Is the Bad Guy!mentioning

confidence: 86%

Which NADPH Oxidase Isoform Is Relevant for Ischemic Stroke? The Case for Nox 2

Kahles

Brandes²

2013

Antioxidants & Redox Signaling

108

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Significance and Recent Advances: Ischemic stroke is the leading cause of disability and third in mortality in industrialized nations. Immediate restoration of cerebral blood flow is crucial to salvage brain tissue, but only few patients are eligible for recanalization therapy. Thus, the need for alternative neuroprotective strategies is huge, and antioxidant interventions have long been studied in this context. Reactive oxygen species (ROS) physiologically serve as signaling molecules, but excessive amounts of ROS, as generated during ischemia/ reperfusion (I/R), contribute to tissue injury. Critical Issues: Nevertheless and despite a strong rational of ROS being a pharmacological target, all antioxidant interventions failed to improve functional outcome in human clinical trials. Antioxidants may interfere with physiological functions of ROS or do not reach the crucial target structures of ROS-induced injury effectively. Future Directions: Thus, a potentially more promising approach is the inhibition of the source of disease-promoting ROS. Within recent years, NADPH oxidases (Nox) of the Nox family have been identified as mediators of neuronal pathology. As, however, several Nox homologs are expressed in neuronal tissue, and as many of the pharmacological inhibitors employed are rather unspecific, the concept of Nox as mediators of brain damage is far from being settled. In this review, we will discuss the contribution of Nox homologs to I/R injury at large as well as to neuronal damage in particular. We will illustrate that the current data provide evidence for Nox2 as the most important NADPH oxidase mediating cerebral injury.

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Section: Nox Homologs In Stroke: Nox2 Is the Bad Guy!mentioning

confidence: 86%

Which NADPH Oxidase Isoform Is Relevant for Ischemic Stroke? The Case for Nox 2

Kahles

Brandes²

2013

Antioxidants & Redox Signaling

108

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“…15,16,34 Neurodegeneration is also thought to play a role in the vascular lesions associated with ischemic retinopathies, and is an emerging area of investigation and therapeutic target in many of these retinal disease models. 18,20,27 Our group previously demonstrated that PPARa activation had a therapeutic effect in DR animal models, and that PPARa played an important role in vascular homeostasis, decreasing leukostasis, vascular leakage, and neovascularization in diabetic and OIR animal models. 4,42 However, PPARa's effect on retinal neurodegeneration was previously unknown.…”

Section: Discussionmentioning

confidence: 99%

“…25,26 Nox 2 and Nox 4 both contribute to neurodegeneration in multiple disease models, and inhibition or ablation of each isoform has been shown to have beneficial effects in Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc. www.iovs.org j ISSN: 1552-5783 diabetic and ischemic retinopathies, including neuroprotection. 27,28 Regulation of Nox family members is complex, and is a topic of intense investigation, as Nox proteins represent a promising therapeutic target for ischemic disease. 29 Hypoxia-inducible factor 1a (HIF-1a) is rapidly degraded in normoxic conditions, but is stabilized in hypoxia.…”

Section: Methodsmentioning

confidence: 99%

Protective and Antioxidant Effects of PPARα in the Ischemic Retina

Moran

Ding

Wang

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Previous studies have demonstrated that peroxisome proliferator-activated receptoralpha (PPARa) agonists have therapeutic effects in diabetic retinopathy, although the mechanism of action remains incompletely understood. The purpose of this study was to evaluate PPARa's protective effects in the ischemic retina, and to delineate its molecular mechanism of action. METHODS.For the oxygen-induced retinopathy (OIR) model, wild-type (WT), and PPARa knockout (PPARa À/À ) mice were exposed to 75% O 2 from postnatal day 7 (P7) to P12 and treated with the PPARa agonist fenofibric acid (Feno-FA) from P12 to P16. At P17, the effects of Feno-FA on retinal glial fibrillary acidic protein (GFAP) expression, apoptotic DNA cleavage, and TUNEL labeling were analyzed. Cultured retinal cells were exposed to CoCl 2 to induce hypoxia, and TUNEL staining and 5-(and-6)-chloromethyl-2 0 ,7 0 -dichlorodihydrofluorescein dye were used to measure apoptosis and reactive oxygen species (ROS) generation. Western blotting was used to measure GFAP levels and cell signaling. RESULTS. Feno-FA decreased retinal apoptosis and oxidative stress in WT but not PPARaÀ/À OIR mice. Peroxisome proliferator-activated receptor-alpha knockout OIR mice showed increased retinal cell death and glial activation in comparison to WT OIR mice. Feno-FA treatment and PPARa overexpression protected cultured retinal cells from hypoxic cell death and decreased ROS levels. Nuclear hypoxia-inducible factor-a (HIF-1a) and nicotine adenine dinucleotide phosphate oxidase-4 (Nox 4) were increased in OIR retinas and downregulated by Feno-FA in WT but not in PPARa À/À mice.CONCLUSIONS. Peroxisome proliferator-activated receptor-alpha has a potent antiapoptotic effect in the ischemic retina. This protective effect may be mediated in part through downregulation of HIF-1a/Nox 4 and consequently alleviation of oxidative stress.

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“…Moreover, retinal I/R injury developed vision loss and even blindness, owing to eternal damage to the retina, particularly retinal neurons 3, 4, 5. Ischaemia blocked blood flow to retina, causing the transient deficiency of oxygen and other physiological nutrients, such as adenosine triphosphate 6. The following reperfusion further aggravated the tissue damage through producing reactive oxygen species (ROS) and pro‐inflammatory mediators, which rendered oxidative stress and inflammation 7, 8.…”

Section: Introductionmentioning

confidence: 99%

Collagen peptide modified carboxymethyl cellulose as both antioxidant drug and carrier for drug delivery against retinal ischaemia/reperfusion injury

Mao

Wang

Wei

et al. 2018

J Cellular Molecular Medi

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Oxidative stress can cause injury in retinal endothelial cells. Carboxymethyl cellulose modified with collagen peptide (CMCC) is of a distinct antioxidant capacity and potentially a good drug carrier. In this study, the protective effects of CMCC against H2O2‐induced injury of primary retinal endothelial cells were investigated. In vitro, we demonstrated that CMCC significantly promoted viability of H2O2‐treated cells, efficiently restrained cellular reactive oxygen species (ROS) production and cell apoptosis. Then, the CMCC was employed as both drug and anti‐inflammatory drug carrier for treatment of retinal ischaemia/reperfusion (I/R) in rats. Animals were treated with CMCC or interleukin‐10‐loaded CMCC (IL‐10@CMCC), respectively. In comparisons, the IL‐10@CMCC treatment exhibited superior therapeutic effects, including better restoration of retinal structural thickness and less retinal apoptosis. Also, chemiluminescence demonstrated that transplantation of IL‐10@CMCC markedly reduced the retinal oxidative stress level compared with CMCC alone and potently recovered the activities of typical antioxidant enzymes, SOD and CAT. Therefore, it could be concluded that CMCC provides a promising platform to enhance the drug‐based therapy for I/R‐related retinal injury.

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Neuroprotection from Retinal Ischemia/Reperfusion Injury by NOX2 NADPH Oxidase Deletion

Abstract: These data demonstrate that the deletion of NOX2 can reduce I/R-induced cell death and preserve retinal GCL neurons after I/R injury. The neuronal cell injury caused by I/R is associated with the activation of ERK and NF-κB signaling mechanisms.

Cited by 67 publications

References 45 publications

Which NADPH Oxidase Isoform Is Relevant for Ischemic Stroke? The Case for Nox 2

Which NADPH Oxidase Isoform Is Relevant for Ischemic Stroke? The Case for Nox 2

Protective and Antioxidant Effects of PPARα in the Ischemic Retina

Collagen peptide modified carboxymethyl cellulose as both antioxidant drug and carrier for drug delivery against retinal ischaemia/reperfusion injury

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