NADPH oxidase in stroke and cerebrovascular disease

Tang, Xiaowu Shirley; Cairns, Belinda; Kim, Jong Youl; Yenari, Midori A.

doi:10.1179/1743132812y.0000000021

Cited by 68 publications

(55 citation statements)

References 79 publications

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“…Similarly, Western blot analyses for the strokewithout-treatment group demonstrated a significant reduction in PDH protein expression at 3 (F [4,30] =3.9; P<0.05) and 24 hours (F [4,30] =2.7; P<0.05) after reperfusion compared with sham-operated group ( Figure 5B). Individual therapies of ethanol or NBO did not significantly reverse this reduction in PDH expression at either time point.…”

Section: Pdh Activity and Protein Expressionmentioning

confidence: 98%

“…Compared with the sham-operated group, PDH enzyme activity was significantly reduced in ischemic rats after reperfusion at 3 (F [4,30] =12.1; P<0.01) and 24 hours (F [4,30] =14.8; P<0.01; Figure 5A). This reduction in PDH activity was only slightly reversed by ethanol or NBO monotherapy.…”

Section: Pdh Activity and Protein Expressionmentioning

confidence: 98%

“…NBO treatment alone did not significantly reduce NOX activity, whereas ethanol by itself reduced NOX activity only at 24 hours. In all ischemic groups, there was a significant increase in protein levels for gp91 phox at 3 (F [4,30] =9.8; P<0.01) and 24 hours (F [4,30] =7.3; P<0.01; Figure 4B), for p47 phox at 3 (F [4,30] =8.3; P<0.01) and 24 hours (F [4,30] =3.6; P<0.05; Figure 4C), and for p67 phox at 3 (F [4,30] =10.9; P<0.01) and 24 hours (F [4,30] =8.3; P<0.01; Figure 4D), respectively, compared with the sham-operated control group. In monotherapy groups, small reductions of p47 phox , p67 phox , and gp91 phox proteins were observed at 3 and 24 hours, whereas combination treatment induced a much greater reduction in all NOX subunits (P<0.01).…”

Section: Nox Activity and Protein Subunit Expressionmentioning

confidence: 99%

“…25,29 The beneficial effect of combination therapy on reduced oxidative stress, in our study, may be attributed to its effect on NOX and PDH, which are important enzymes related to ROS production and oxidative metabolism. NOX, a membrane-bound enzyme complex, has been shown to exacerbate ischemia/reperfusion injury 30 and is a well-known major source of ROS generation in stroke. NOX is a multicomponent cytoplasmic enzyme (p47 phox , p67 phox , p40 phox , and Rac2) that, on phosphorylation of the p47 phox subunit, 31 forms a complex and translocates to the plasma membrane to dock with specific plasma membrane subunits such as p91 phox .…”

Section: Strokementioning

confidence: 99%

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Synergetic Neuroprotection of Normobaric Oxygenation and Ethanol in Ischemic Stroke Through Improved Oxidative Mechanism

et al. 2013

Stroke

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Background and Purpose— Normobaric oxygenation (NBO) and ethanol both provide neuroprotection in stroke. We evaluated the enhanced neuroprotective effect of combining these 2 treatments in a rat stroke model. Methods— Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 2 hours. Reperfusion was then established and followed by treatment with either (1) an intraperitoneal injection of ethanol (1.0 g/kg), (2) NBO treatment (2-hour duration), or (3) NBO plus ethanol. The extent of brain injury was determined by infarct volume and motor performance. Oxidative metabolism was determined by ADP/ATP ratios, reactive oxygen species levels, nicotinamide adenine dinucleotide phosphate oxidase activity, and pyruvate dehydrogenase activity. Protein expression of major nicotinamide adenine dinucleotide phosphate oxidase subunits (p47 phox , gp91 phox , and p67 phox ) and the enzyme pyruvate dehydrogenase was evaluated through Western immunoblotting. Results— NBO and ethanol monotherapies each demonstrated reductions as compared to stroke without treatment in infarct volume (36.7% and 37.9% vs 48.4%) and neurological deficits (score of 6.4 and 6.5 vs 8.4); however, the greatest neuroprotection (18.8% of infarct volume and 4.4 neurological deficit) was found in animals treated with combination therapy. This neuroprotection was associated with the largest reductions in ADP/ATP ratios, reactive oxygen species levels, and nicotinamide adenine dinucleotide phosphate oxidase activity, and the largest increase in pyruvate dehydrogenase activity. Conclusions— Combination therapy with NBO and ethanol enhances the neuroprotective effect produced by each therapy alone. The mechanism behind this synergistic action is related to changes in cellular metabolism after ischemia reperfusion. NBO plus ethanol is attractive for clinical study because of its ease of use, tolerability, and tremendous neuroprotective potential in stroke.

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Section: Pdh Activity and Protein Expressionmentioning

confidence: 98%

Section: Pdh Activity and Protein Expressionmentioning

confidence: 98%

Section: Nox Activity and Protein Subunit Expressionmentioning

confidence: 99%

Section: Strokementioning

confidence: 99%

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Synergetic Neuroprotection of Normobaric Oxygenation and Ethanol in Ischemic Stroke Through Improved Oxidative Mechanism

et al. 2013

Stroke

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“…NOX1-deficient mice showed no difference in sub-cortical cerebral infarct volume, but a four-fold greater cortical infarct volume. Apocynin (116,167,296,341) and the small molecule NOX inhibitor, VAS2870 (140) improved outcome in the mouse models of ischemic stroke. The reported discrepancies among studies may relate to the duration of ischemia before reperfusion, and, in general, suggest that NOX2 and/or NOX4 inhibition is likely to be most effective when administered early after stroke.…”

Section: Ischemic Conditionsmentioning

confidence: 99%

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Diebold

Smith

Yang

et al. 2015

Antioxidants & Redox Signaling

106

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Significance: NOX2 is important for host defense, and yet is implicated in a large number of diseases in which inflammation plays a role in pathogenesis. These include acute and chronic lung inflammatory diseases, stroke, traumatic brain injury, and neurodegenerative diseases, including Alzheimer's and Parkinson's Diseases. Recent Advances: Recent drug development programs have targeted several NOX isoforms that are implicated in a variety of diseases. The focus has been primarily on NOX4 and NOX1 rather than on NOX2, due, in part, to concerns about possible immunosuppressive side effects. Nevertheless, NOX2 clearly contributes to the pathogenesis of many inflammatory diseases, and its inhibition is predicted to provide a novel therapeutic approach. Critical Issues: Possible side effects that might arise from targeting NOX2 are discussed, including the possibility that such inhibition will contribute to increased infections and/or autoimmune disorders. The state of the field with regard to existing NOX2 inhibitors and targeted development of novel inhibitors is also summarized. Future Directions: NOX2 inhibitors show particular promise for the treatment of inflammatory diseases, both acute and chronic. Theoretical side effects include pro-inflammatory and autoimmune complications and should be considered in any therapeutic program, but in our opinion, available data do not indicate that they are sufficiently likely to eliminate NOX2 as a drug target, particularly when weighed against the seriousness of many NOX2-related indications. Model studies demonstrating efficacy with minimal side effects are needed to encourage future development of NOX2 inhibitors as therapeutic agents. Antioxid. Redox Signal. 23,

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The role of the microglia in acute CNS injury

2014

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Microglia are considered the brain’s resident immune cell involved in immune defense, immunocompetence, and phagocytosis. They maintain tissue homeostasis within the brain and spinal cord under normal condition and serves as its initial host defense system. However, when the central nervous system (CNS) faces injury, microglia respond through signaling molecules expressed or released by neighboring cells. Microglial responses are dual in nature. They induce a nonspecific immune response that may exacerbate CNS injury, especially in the acute stages, but are also essential to CNS recovery and repair. The full range of microglial mechanisms have yet to be clarified, but there is accumulating knowledge about microglial activation in acute CNS injury. Microglial responses require hours to days to fully develop, and may present a therapeutic target for intervention with a much longer window of opportunity compare to other neurological treatments. The challenge will be to find ways to selectively suppress the deleterious effects of microglial activation without compromising its beneficial functions. This review aims to provide an overview of the recent progress relating on the deleterious and beneficial effect of microglia in the setting of acute CNS injury and the potential therapeutic intervention against microglial activation to CNS injury.

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NADPH oxidase in stroke and cerebrovascular disease

Cited by 68 publications

References 79 publications

Synergetic Neuroprotection of Normobaric Oxygenation and Ethanol in Ischemic Stroke Through Improved Oxidative Mechanism

Synergetic Neuroprotection of Normobaric Oxygenation and Ethanol in Ischemic Stroke Through Improved Oxidative Mechanism

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

The role of the microglia in acute CNS injury

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