Central Nervous System Injury and Nicotinamide Adenine Dinucleotide Phosphate Oxidase: Oxidative Stress and Therapeutic Targets

Leden, Ramona E. von; Yauger, Young J; Khayrullina, Guzal; Byrnes, Kimberly R.

doi:10.1089/neu.2016.4486

Cited by 68 publications

(54 citation statements)

References 94 publications

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“…In general, 5 isoforms of NADPH oxidase (NOX) family have been identified (NOX1, 2, 3, and 4, and DUOX 2), and are shown to express in the spinal cord. Microglia are reported to express only NOX2 and NOX4 in the spinal cord and are upregulated after traumatic CNS injury [40,41]. NOX2 is present in all cell types, NOX3 is found only in neurons, and NOX4 is found only in acute glial cells [42].…”

Section: Discussionmentioning

confidence: 99%

Advanced oxidation protein products induce microglia-mediated neuroinflammation via MAPKs-NF-κB signaling pathway and pyroptosis after secondary spinal cord injury

Liu

Yao

Jiang

et al. 2020

J Neuroinflammation

233

127

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Background: Inflammatory response mediated by oxidative stress is considered as an important pathogenesis of spinal cord injury (SCI). Advanced oxidation protein products (AOPPs) are novel markers of oxidative stress and their role in inflammatory response after SCI remained unclear. This study aimed to investigate the role of AOPPs in SCI pathogenesis and explore the possible underlying mechanisms. Methods: A C5 hemi-contusion injury was induced in Sprague-Dawley rats to confirm the involvement of AOPPs after SCI. For in vivo study, apocynin, the NADPH oxidase inhibitor was used to study the neuroprotective effects after SCI. For in vitro study, the BV2 microglia cell lines were pretreated with or without the inhibitor or transfected with or without small interference RNA (siRNA) and then stimulated with AOPPs. A combination of molecular and histological methods was used to clarify the mechanism and explore the signaling pathway both in vivo and in vitro. One-way analysis of variance (ANOVA) was conducted with Bonferroni post hoc tests to examine the differences between groups. Results: The levels of AOPPs in plasma and cerebrospinal fluid as well as the contents in the spinal cord showed significant increase after SCI. Meanwhile, apocynin ameliorated tissue damage in the spinal cord after SCI, improving the functional recovery. Immunofluorescence staining and western blot analysis showed activation of microglia after SCI, which was in turn inhibited by apocynin. Pretreated BV2 cells with AOPPs triggered excessive generation of reactive oxygen species (ROS) by activating NADPH oxidase. Increased ROS induced p38 MAPK and JNK phosphorylation, subsequently triggering nuclear translocation of NF-κB p65 to express pro-inflammatory cytokines. Also, treatment of BV2 cells with AOPPs induced NLRP3 inflammasome activation and cleavage of Gasdermin-d (GSDMD), causing pyroptosis. This was confirmed by cleavage of caspase-1, production of downstream mature interleukin (IL)-1β and IL-18 as well as rupture of rapid cell membrane.

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Section: Discussionmentioning

confidence: 99%

Advanced oxidation protein products induce microglia-mediated neuroinflammation via MAPKs-NF-κB signaling pathway and pyroptosis after secondary spinal cord injury

Liu

Yao

Jiang

et al. 2020

J Neuroinflammation

233

127

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“…In injured cortex NOX2 is highly up-regulated in microglia/macrophages that co-express M1-like, or mixed M1-/M2-like activation markers, but not with single M2-like activation markers (Kumar et al, 2015). Increasingly, NOX2 is being recognized as an important therapeutic target for CNS injury (von Leden et al, 2016), and pharmacological or genetic intervention studies demonstrate that NOX2 inhibition after TBI is neuroprotective, mediated, in part, by targeting secondary neuroinflammation and microglial activation (Dohi et al, 2010; Loane et al, 2013; Lu et al, 2014; Zhang et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

NOX2 drives M1-like microglial/macrophage activation and neurodegeneration following experimental traumatic brain injury

Kumar

Barrett

Álvarez‐Croda

et al. 2016

Brain, Behavior, and Immunity

160

140

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Following traumatic brain injury (TBI), activation of microglia and peripherally derived inflammatory macrophages occurs in association with tissue damage. This neuroinflammatory response may have beneficial or detrimental effects on neuronal survival, depending on the functional polarization of these cells along a continuum from M1-like to M2-like activation states. The mechanisms that regulate M1-like and M2-like activation after TBI are not well understood, but appear in part to reflect the redox state of the lesion microenvironment. NADPH oxidase (NOX2) is a critical enzyme system that generates reactive oxygen species in microglia/macrophages. After TBI, NOX2 is strongly up-regulated in M1-like, but not in M2-like polarized cells. Therefore, we hypothesized that NOX2 drives M1-like neuroinflammation and contributes to neurodegeneration and loss of neurological function after TBI. In the present studies we inhibited NOX2 activity using NOX2-knockout mice or the selective peptide inhibitor gp91ds-tat. We show that NOX2 is highly up-regulated in infiltrating macrophages after injury, and that NOX2 deficiency reduces markers of M1-like activation, limits tissue loss and neurodegeneration, and improves motor recovery after moderate-level control cortical injury (CCI). NOX2 deficiency also promotes M2-like activation after CCI, through increased IL-4Rα signaling in infiltrating macrophages, suggesting that NOX2 acts as a critical switch between M1- and M2-like activation states after TBI. Administration of gp91ds-tat to wild-type CCI mice starting at 24 hours post-injury reduces deficits in cognitive function and increased M2-like activation in the hippocampus. Collectively, our data indicate that increased NOX2 activity after TBI drives M1-like activation that contributes to inflammatory-mediated neurodegeneration, and that inhibiting this pathway provides neuroprotection, in part by altering M1-/M2-like balance towards the M2-like neuroinflammatory response.

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“…[41] In fact, SOD enzymatic activity has been shown to be neuroprotective following SCI, [42, 43] with administration of SOD enzyme rescuing motor neuron health in the injured spinal cord. [42] In this study the SOD-loaded porous polymersomes were administered immediately after injury, although oxidative stress following neural injury is thought to occur within hours after injury, [38, 44] it is unknown if administration of these polymersomes later after injury would be as effective, when pain and axonal damage are established. However, these studies demonstrate that SOD-encapsulated porous particles can be used as a novel potential pain treatment, that is more effective than treatment with free antioxidant alone.…”

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confidence: 99%

Superoxide Dismutase‐Loaded Porous Polymersomes as Highly Efficient Antioxidants for Treating Neuropathic Pain

Kartha

Yan

Weisshaar

et al. 2017

Adv Healthcare Materials

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Highly efficient antioxidants based on superoxide dismutase (SOD) -loaded porous polymersomes are developed for treating neuropathic pain. The SOD-loaded porous polymersomes are highly permeable to superoxide radical, while retaining the antioxidant enzyme within their aqueous interiors. Administration of the antioxidant porous polymersomes following a painful nerve root compression is substantially more effective in preventing the onset of pain in rats than comparable or higher doses of free SOD alone.

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Central Nervous System Injury and Nicotinamide Adenine Dinucleotide Phosphate Oxidase: Oxidative Stress and Therapeutic Targets

Cited by 68 publications

References 94 publications

Advanced oxidation protein products induce microglia-mediated neuroinflammation via MAPKs-NF-κB signaling pathway and pyroptosis after secondary spinal cord injury

Advanced oxidation protein products induce microglia-mediated neuroinflammation via MAPKs-NF-κB signaling pathway and pyroptosis after secondary spinal cord injury

NOX2 drives M1-like microglial/macrophage activation and neurodegeneration following experimental traumatic brain injury

Superoxide Dismutase‐Loaded Porous Polymersomes as Highly Efficient Antioxidants for Treating Neuropathic Pain

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