NADPH oxidase inhibition improves neurological outcome in experimental traumatic brain injury

Lu, Xinyu; Wang, Handong; Xu, Jianguo; Ding, Ke; Li, Tao

doi:10.1016/j.neuint.2014.02.006

Cited by 53 publications

(36 citation statements)

References 27 publications

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“…TBI rapidly up-regulates NOX2 enzyme subunits in injured neurons and astrocytes during the acute phase after injury, followed by high NOX2 expression in amoeboid-like microgila/macrophages during the sub-acute and chronic periods (Dohi et al, 2010; Kumar et al, 2015; Loane et al, 2014). NOX2 inhibition by pharmacological or genetic means is neuroprotective (Dohi et al, 2010; Loane et al, 2013; Lu et al, 2014; Zhang et al, 2012), in part, by modulating secondary neuroinflammation and microglial activation. Previously, it has been shown that NOX2 deficiency resulted in reduced O 2− and peroxynitrite metabolites in the injured cortex; effects that were associated with reduced neuronal cell death and microglial activation (Dohi et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

“…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%

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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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Section: Resultsmentioning

confidence: 99%

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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“…Furthermore, combination therapies that inhibit both ER stress and oxidative stress might be a potentially better therapeutic strategy for preventing post-stroke and post-TBI secondary brain damage. Many antioxidant drugs like Edaravone and apocynin were shown to curtail ischemic and traumatic brain damage effectively (152–156). …”

Section: Therapeutic Opportunities For Neuroprotection By Modulatimentioning

confidence: 99%

Crosstalk Between Endoplasmic Reticulum Stress, Oxidative Stress, and Autophagy: Potential Therapeutic Targets for Acute CNS Injuries

2014

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Endoplasmic reticulum (ER) stress induces a variety of neuronal cell death pathways that play a critical role in the pathophysiology of Stroke. ER stress occurs when unfolded/misfolded proteins accumulate and the folding capacity of ER chaperones exceeds the capacity of ER lumen to facilitate their disposal. As a consequence, a complex set of signaling pathways will be induced that transmit from ER to cytosol and nucleus to compensate damage and to restore the normal cellular homeostasis, collectively known as unfolded protein response (UPR). However, failure of UPR due to severe or prolonged stress leads to cell death. Following acute CNS injuries, chronic disturbances in protein folding and oxidative stress prolong ER stress leading to sustained ER dysfunction and neuronal cell death. While ER stress responses have been well studied after stroke, there is an emerging need to study the association of ER stress with other cell pathways that exacerbate neuronal death after an injury. In this review we summarize the current understanding of the role for ER stress in acute brain injuries, highlighting the diverse molecular mechanisms associated with ER stress and its relation to oxidative stress and autophagy. We also discussed the existing and developing therapeutic options aimed to reduce ER stress to protect the CNS after acute injuries.

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“…entry has been shown to play a critical role in the activation of NADPH oxidase and the subsequent production of superoxide in neutrophils (Brechard and Tschirhart 2008). Recently, mounting studies demonstrated that ROS generated by over-activated NADPH oxidase contributes significantly to oxidative stress and neuronal damage in CNS (Brennan et al 2009;Ansari and Scheff 2011;Hill et al 2014), and genetic or pharmacological modulation of NADPH oxidase has been demonstrated to considerably attenuate cerebral oxidative injury (Behrens et al 2007;Cairns et al 2012;Lu et al 2014). With the growing research on NADPH oxidase, its role in pathophysiological dysfunction of neural cells has attracted high attentions.…”

Section: Introductionmentioning

confidence: 99%

Propofol Protects Against H2O2-Induced Oxidative Injury in Differentiated PC12 Cells via Inhibition of Ca2+-Dependent NADPH Oxidase

et al. 2015

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Propofol (2,6-diisopropylphenol) is a widely used general anesthetic with anti-oxidant activities. This study aims to investigate protective capacity of propofol against hydrogen peroxide (H2O2)-induced oxidative injury in neural cells and whether the anti-oxidative effects of propofol occur through a mechanism involving the modulation of NADPH oxidase (NOX) in a manner of calcium-dependent. The rat differentiated PC12 cell was subjected to H2O2 exposure for 24 h to mimic a neuronal in vitro model of oxidative injury. Our data demonstrated that pretreatment of PC12 cells with propofol significantly reversed the H2O2-induced decrease in cell viability, prevented H2O2-induced morphological changes, and reduced the ratio of apoptotic cells. We further found that propofol attenuated the accumulation of malondialdehyde (biomarker of oxidative stress), counteracted the overexpression of NOX core subunit gp91(phox) (NOX2) as well as the NOX activity following H2O2 exposure in PC12 cells. In addition, blocking of L-type Ca(2+) channels with nimodipine reduced H2O2-induced overexpression of NOX2 and caspase-3 activation in PC12 cells. Moreover, NOX inhibitor apocynin alone or plus propofol neither induces a significant downregulation of NOX activity nor increases cell viability compared with propofol alone in the PC12 cells exposed to H2O2. These results demonstrate that the protective effects of propofol against oxidative injury in PC12 cells are mediated, at least in part, through inhibition of Ca(2+)-dependent NADPH oxidase.

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NADPH oxidase inhibition improves neurological outcome in experimental traumatic brain injury

Cited by 53 publications

References 27 publications

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

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

Crosstalk Between Endoplasmic Reticulum Stress, Oxidative Stress, and Autophagy: Potential Therapeutic Targets for Acute CNS Injuries

Propofol Protects Against H2O2-Induced Oxidative Injury in Differentiated PC12 Cells via Inhibition of Ca2+-Dependent NADPH Oxidase

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