NADPH Oxidase-4 Maintains Neuropathic Pain after Peripheral Nerve Injury

Kallenborn-Gerhardt, Wiebke; Schröder, Katrin; Turco, Domenico Del; Lu, Ruirui; Kynast, Katharina L.; Kosowski, Judith; Niederberger, Ellen; Shah, Ajay M.; Brandes, Ralf P.; Geißlinger, Gerd; Schmidtko, Achim

doi:10.1523/jneurosci.6227-11.2012

Cited by 102 publications

(90 citation statements)

References 69 publications

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“…In the spared nerve injury, NOX4-dependent H 2 O 2 was measured in sciatic nerve while a decrease in axon size peripheral dismyelination of the sciatic nerve was observed. All these features were partially reduced in NOX4-deficient mice, although microglia activation was comparable between NOX4-deficient and control littermates 14 days after spared nerve injury (87). Thus, both microglial NOX2 and neuronal NOX4 might be involved in the development of neuropathic pain.…”

Section: Painmentioning

confidence: 91%

“…For most parts, there is no detailed knowledge with regard to the expression of NOX isoforms in neuronal subtypes. Possible exceptions to this are the relatively well-documented expression of NOX1 in dopaminergic (DA) neurons (37), NOX2 expression in CA1 hippocampal neurons of old mice (50), the NOX2 subunit p47 phox in hippocampal neurons (22) as well as in pyramidal neurons of socially isolated rats (145), and NOX4 expression in dorsal root ganglion (DRG) neurons (87) and in basal ganglion and cortical neurons after stroke (94). The subcellular localization of NOX enzymes in neurons is still relatively unexplored; however, there is some evidence for a synaptic localization of NOX2 (157).…”

Section: Physiological Role Of Nox In Cnsmentioning

confidence: 99%

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New Insights onNOXEnzymes in the Central Nervous System

Nayernia

Jaquet

Krause

2014

Antioxidants & Redox Signaling

245

231

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Significance: There is increasing evidence that the generation of reactive oxygen species (ROS) in the central nervous system (CNS) involves the NOX family of nicotinamide adenine dinucleotide phosphate oxidases. Controlled ROS generation appears necessary for optimal functioning of the CNS through fine-tuning of redoxsensitive signaling pathways, while overshooting ROS generation will lead to oxidative stress and CNS disease. Recent Advances: NOX enzymes are not only restricted to microglia (i.e. brain phagocytes) but also expressed in neurons, astrocytes, and the neurovascular system. NOX enzymes are involved in CNS development, neural stem cell biology, and the function of mature neurons. While NOX2 appears to be a major source of pathological oxidative stress in the CNS, other NOX isoforms might also be of importance, for example, NOX4 in stroke. Globally speaking, there is now convincing evidence for a role of NOX enzymes in various neurodegenerative diseases, cerebrovascular diseases, and psychosis-related disorders. Critical Issues: The relative importance of specific ROS sources (e.g., NOX enzymes vs. mitochondria; NOX2 vs. NOX4) in different pathological processes needs further investigation. The absence of specific inhibitors limits the possibility to investigate specific therapeutic strategies. The uncritical use of non-specific inhibitors (e.g., apocynin, diphenylene iodonium) and poorly validated antibodies may lead to misleading conclusions. Future Directions: Physiological and pathophysiological studies with cell-type-specific knock-out mice will be necessary to delineate the precise functions of NOX enzymes and their implications in pathomechanisms. The development of CNS-permeant, specific NOX inhibitors will be necessary to advance toward therapeutic applications. Antioxid. Redox Signal. 20, 2815Signal. 20, -2837

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Section: Painmentioning

confidence: 91%

Section: Physiological Role Of Nox In Cnsmentioning

confidence: 99%

New Insights onNOXEnzymes in the Central Nervous System

Nayernia

Jaquet

Krause

2014

Antioxidants & Redox Signaling

245

231

View full text Add to dashboard Cite

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“…Finally, NOX4 inhibition was suggested as therapy for the treatment of neuropathic pain (82). The effectiveness of preventions was shown using NOX4 KO animals.…”

Section: Nox3-a Target Candidate For Cisplatin-induced Hearing Lossmentioning

confidence: 99%

Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement

Altenhöfer

Radermacher

Kleikers

et al. 2015

Antioxidants & Redox Signaling

442

417

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Significance: Oxidative stress, an excess of reactive oxygen species (ROS) production versus consumption, may be involved in the pathogenesis of different diseases. The only known enzymes solely dedicated to ROS generation are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases with their catalytic subunits (NOX). After the clinical failure of most antioxidant trials, NOX inhibitors are the most promising therapeutic option for diseases associated with oxidative stress. Recent Advances: Historical NADPH oxidase inhibitors, apocynin and diphenylene iodonium, are un-specific and not isoform selective. Novel NOX inhibitors stemming from rational drug discovery approaches, for example, GKT137831, ML171, and VAS2870, show improved specificity for NADPH oxidases and moderate NOX isoform selectivity. Along with NOX2 docking sequence (NOX2ds)-tat, a peptide-based inhibitor, the use of these novel small molecules in animal models has provided preliminary in vivo evidence for a pathophysiological role of specific NOX isoforms. Critical Issues: Here, we discuss whether novel NOX inhibitors enable reliable validation of NOX isoforms' pathological roles and whether this knowledge supports translation into pharmacological applications. Modern NOX inhibitors have increased the evidence for pathophysiological roles of NADPH oxidases. However, in comparison to knockout mouse models, NOX inhibitors have limited isoform selectivity. Thus, their use does not enable clear statements on the involvement of individual NOX isoforms in a given disease. Future Directions: The development of isoform-selective NOX inhibitors and biologicals will enable reliable validation of specific NOX isoforms in disease models other than the mouse. Finally, GKT137831, the first NOX inhibitor in clinical development, is poised to provide proof of principle for the clinical potential of NOX inhibition. Antioxid. Redox Signal. 23, 406-427.

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“…For example, genetic variations and poly morphisms in endogenous antioxidant enzymes have been associated with an increased susceptibility to diabetic neuropathy 62 . Potential sources of ROS in peripheral nerves include the polyol pathway, the mitochondrial electron transport chain, RAGE (receptor for advanced glycosylation end products) signalling, and NADPH oxidases and nitric oxide synthases [63][64][65] . Schwann cells are increasingly being recognized as an important site of ROS production, which, in this context, affects Schwann cell function and their interactions with other cell types within the nerve trunk.…”

Section: Oxidative Stress and Mitochondrial Dysfunctionmentioning

confidence: 99%

Schwann cell interactions with axons and microvessels in diabetic neuropathy

et al. 2017

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The incidence of diabetes mellitus has increased dramatically over the past two to three decades. According to the International Diabetes Federation Diabetes Atlas, 415 million people worldwide had diabetes in 2015, and this number is expected to grow by 5% annually, predominantly as a result of increasing prevalence of type 2 diabetes. Furthermore, an estimated 100 million Europeans and 80 million Americans have impaired glucose tolerance or prediabetes. Few people die from acute diabetes in countries with comprehensive health care systems, but the disease is inflicting a huge medical, social and economic burden on society owing to the need for lifelong treatment of its systemic consequences and the insidious development of multi-organ damage.Peripheral neuropathy (BOXES 1,2) is a common but often neglected complication of long-term diabetes, and the lack of treatment options reflects an incomplete understanding of the pathogenic mechanisms. Hyperglycaemia is generally accepted as the primary pathogenic insult in type 1 and type 2 diabetic neuropathy, although roles are emerging for other factors, such as impaired insulin signalling, hypertension and dyslipidaemia (particularly for type 2 diabetes), which might precede overt hyperglycaemia 1 . Many preclinical studies, and occasional clinical studies, have indicated that diabetic neuropathy -like diabetic nephropathy and retinopathy -results from microvascular disease, with a focus on axonal degeneration as a consequence of ischaemia and/or hypoxia. This mechanism, however, is likely to be only one aspect of a more complex pathogenesis.The earliest descriptions of pathology in diabetic neuropathy indicated that Schwannopathy accompanied axonal degeneration. The majority of clinical and basic research in diabetic neuropathy since then has focused on the effects on neurons. However, accumulating data from research into the development and regeneration of the PNS has identified Schwann cells as equally indispensable components that maintain neuronal structure and function, nourish axons, and promote survival and growth upon injury. The early reports from 1979 that demonstrated morphological changes in Schwann cells in human diabetic neuropathy 2 are now supported by an increased awareness of molecular alterations in Schwann cells during diabetes 3 . Schwann cells express a wide range of receptors and, when they sense insults or danger signals, they upregulate synthesis and secretion of factors that stimulate neuroprotection, regrowth and remyelination, or factors that aggravate disease phenotypes 4 . The most recent studies have demonstrated that Schwann cells regulate many aspects of axonal function, so that disruption of their metabolism by diabetes results in the accumulation of neurotoxic intermediates and compromises production of neuronal support factors, contributing to axonal degeneration, endothelial dysfunction and diabetic neuropathy. Abstract | The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annu...

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NADPH Oxidase-4 Maintains Neuropathic Pain after Peripheral Nerve Injury

Cited by 102 publications

References 69 publications

New Insights onNOXEnzymes in the Central Nervous System

New Insights onNOXEnzymes in the Central Nervous System

Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement

Schwann cell interactions with axons and microvessels in diabetic neuropathy

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