NADPH oxidase inhibitor DPI is neuroprotective at femtomolar concentrations through inhibition of microglia over-activation

Li, Qian; Gao, Xi; Pei, Zhong; Wu, Xing; Block, Michelle L.; Wilson, Belinda; Hong, Jau Shyong; Flood, Patrick M.

doi:10.1016/s1353-8020(08)70023-3

Cited by 51 publications

(43 citation statements)

References 18 publications

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“…Furthermore, DPI treatment reduces endothelial cell adhesion molecule expression, leading to a reduction in permeability to circulating cells and improved BBB integrity [28]. One recent study has found that femtomolar concentrations of DPI inhibit NADPH oxidase in microglia, and reduce LPS-induced TNFα release and nitric oxide production [16]. Furthermore, this study found that LPS-induced microglial neurotoxicity could be blocked by DPI [16].…”

Section: Nadph Oxidasementioning

confidence: 73%

“…Activation of the NOX2 complex involves 2 steps: 1) up-regulation of expression of the individual protein components and 2) protein kinase C (PKC)-or mitogen activated protein kinase-mediated phosphorylation of the cytosolic components [16]. Phosphorylated subunits are then translocated to the membrane, where they assemble…”

Section: Nadph Oxidasementioning

confidence: 99%

“…One recent study has found that femtomolar concentrations of DPI inhibit NADPH oxidase in microglia, and reduce LPS-induced TNFα release and nitric oxide production [16]. Furthermore, this study found that LPS-induced microglial neurotoxicity could be blocked by DPI [16]. These effects were found to be preceded by a reduction in extracellular signal-related kinase (ERK) phosphorylation, suggesting that ultra-low DPI concentrations may act on the upstream events of NADPH oxidase activity (in addition to or instead of it) through direct activity at the NADPH oxidase enzyme.…”

Section: Nadph Oxidasementioning

confidence: 99%

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Novel Neuroinflammatory Targets in the Chronically Injured Spinal Cord

Pajoohesh‐Ganji

Byrnes

2011

Neurotherapeutics

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Summary: Injury to the spinal cord is known to result in inflammation. To date, the preponderance of research has focused on the acute neuroinflammatory response, which begins immediately and is believed to terminate within hours to (at most) days after the injury. However, recent studies have demonstrated that postinjury inflammation is not restricted to the first few hours or days after injury, but can last for months to years after a spinal cord injury (SCI). These chronic studies have revealed that increased numbers of inflammatory cells, such as microglia and macrophages, and inflammatory factors, including cytokines, chemokines, and enzyme products are found at markedly delayed times after injury. Here we review experimental work on a selection of the novel inflammatory factors observed chronically after SCI, including the nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase enzyme and galectin-3. We will discuss the role of these proteins in inflammation with regard to both detrimental and beneficial effects of neuroinflammation after injury. Finally, the potential of these proteins to serve as therapeutic targets will be considered, and a novel therapeutic approach (i.e., the agonist for metabotropic glutamate receptor 5 [mGluR5], [RS]-2-Chloro-5-hydroxyphenylglycine [CHPG]) will be discussed. This review will demonstrate the expression and activity profiles, roles in potentiation of injury, and therapy studies of these inflammatory factors suggest that not only are these chronically expressed factors viable targets for SCI treatment, but that the therapeutic window is broader than has previously been thought.

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Section: Nadph Oxidasementioning

confidence: 73%

Section: Nadph Oxidasementioning

confidence: 99%

Section: Nadph Oxidasementioning

confidence: 99%

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Novel Neuroinflammatory Targets in the Chronically Injured Spinal Cord

Pajoohesh‐Ganji

Byrnes

2011

Neurotherapeutics

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“…One of the first identified NADPH oxidase inhibitors, still widely used in in vitro experiments, is DPI, which inhibits NOX activity (92,119). DPI suppressed ROS production by NOX4 and significantly decreased the radiation-induced expression of a-smooth muscle actin and fibronectin in human lung fibroblasts (112).…”

Section: Small-molecule Inhibitorsmentioning

confidence: 99%

NOX Modifiers—Just a Step Away from Application in the Therapy of Airway Inflammation?

Wieczfińska

Sokołowska

Pawliczak

2015

Antioxidants & Redox Signaling

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Significance: NADPH oxidase (NOX) enzymes, which are widely expressed in different airway cell types, not only contribute to the maintenance of physiological processes in the airways but also participate in the pathogenesis of many acute and chronic diseases. Therefore, the understanding of NOX isoform regulation, expression, and the manner of their potent inhibition might lead to effective therapeutic approaches. Recent Advances: The study of the role of NADPH oxidases family in airway physiology and pathophysiology should be considered as a work in progress. While key questions still remain unresolved, there is significant progress in terms of our understanding of NOX importance in airway diseases as well as a more efficient way of using NOX modifiers in human settings. Critical Issues: Agents that modify the activity of NADPH enzyme components would be considered useful tools in the treatment of various airway diseases. Nevertheless, profound knowledge of airway pathology, as well as the mechanisms of NOX regulation is needed to develop potent but safe NOX modifiers. Future Directions: Many compounds seem to be promising candidates for development into useful therapeutic agents, but their clinical potential is yet to be demonstrated. Further analysis of basic mechanisms in human settings, high-throughput compound scanning, clinical trials with new and existing molecules, and the development of new drug delivery approaches are the main directions of future studies on NOX modifiers. In this article, we discuss the current knowledge with regard to NOX isoform expression and regulation in airway inflammatory diseases as well as the aptitudes and therapeutic potential of NOX modifiers. Antioxid. Redox Signal. 23,[428][429][430][431][432][433][434][435][436][437][438][439][440][441][442][443][444][445]

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“…This is because DA neurons appear to have an intrinsic sensitivity to complex I defects based on studies that demonstrate the selective neurotoxic effects of the pesticide rotenone on DA neurons only, despite the fact that rotenone inhibits complex I throughout the brain (Sherer, Betarbet et al 2002). However, even direct inhibition of complex-I by MPTP in DA neurons results in neurodegeneration that is primarily inflammatory in nature (Ghosh, Roy et al 2007;Qian, Gao et al 2007;Qian and Flood 2008). Further evidence of the key role of inflammation in PD is seen in other features of the disease.…”

mentioning

confidence: 99%