A combination antioxidant therapy to inhibit NOX2 and activate Nrf2 decreases secondary brain damage and improves functional recovery after traumatic brain injury

Chandran, Raghavendar; Kim, Tae-Hee; Mehta, Suresh L.; Udho, Eshwar; Chanana, Vishal; Cengiz, Pelin; Kim, HwuiWon; Kim, Chanul; Vemuganti, Raghu

doi:10.1177/0271678x17738701

Cited by 63 publications

(59 citation statements)

References 68 publications

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“…5) and -Syn −/− mice (Fig. 8), all 3-to 4-month-old males, were subjected to the MWM test to examine poststroke spatial learning and memory capabilities (32). The test consists of eight blocks of testing over 4 days, followed by a probe trial.…”

Section: Mwm Testmentioning

confidence: 99%

The microRNA miR-7a-5p ameliorates ischemic brain damage by repressing α-synuclein

et al. 2018

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Ischemic stroke, which is caused by a clot that blocks blood flow to the brain, can be severely disabling and sometimes fatal. We previously showed that transient focal ischemia in a rat model induces extensive temporal changes in the expression of cerebral microRNAs, with a sustained decrease in the abundance of miR-7a-5p (miR-7). Here, we evaluated the therapeutic efficacy of a miR-7 mimic oligonucleotide after cerebral ischemia in rodents according to the Stroke Treatment Academic Industry Roundtable (STAIR) criteria. Rodents were injected locally or systemically with miR-7 mimic before or after transient middle cerebral artery occlusion. Decreased miR-7 expression was observed in both young and aged rats of both sexes after cerebral ischemia. Pre- or postischemic treatment with miR-7 mimic decreased the lesion volume in both sexes and ages studied. Furthermore, systemic injection of miR-7 mimic into mice at 30 min (but not 2 hours) after cerebral ischemia substantially decreased the lesion volume and improved motor and cognitive functional recovery with minimal peripheral toxicity. The miR-7 mimic treatment substantially reduced the postischemic induction of α-synuclein (α-Syn), a protein that induces mitochondrial fragmentation, oxidative stress, and autophagy that promote neuronal cell death. Deletion of the gene encoding α-Syn abolished miR-7 mimic–dependent neuroprotection and functional recovery in young male mice. Further analysis confirmed that the transcript encoding α-Syn was bound and repressed by miR-7. Our findings suggest that miR-7 mimics may therapeutically minimize stroke-induced brain damage and disability.

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Section: Mwm Testmentioning

confidence: 99%

The microRNA miR-7a-5p ameliorates ischemic brain damage by repressing α-synuclein

et al. 2018

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“…Furthermore, studies on cognitive deficits in non-vascular disease demonstrated that increased NOX2 and p47phox expression and activation was involved in cognitive impairment in traumatic brain injury (TBI) [ 116 , 117 , 118 , 119 ], various encephalopathies [ 120 , 121 , 122 , 123 ], and metabolic diseases [ 13 , 124 , 125 ]. Chandran at al.…”

Section: Association Of Nadph Oxidase In Cognitive Impairmentmentioning

confidence: 99%

“…Chandran at al. [ 116 ] reported that NOX2 increased and transcription factor Nrf2 that decreased ROS were induced after TBI. The combination therapy (NOX inhibitor apocynin + Nrf2 activator TBHQ) improved cognitive dysfunction in TBI [ 116 ].…”

Section: Association Of Nadph Oxidase In Cognitive Impairmentmentioning

confidence: 99%

“…[ 116 ] reported that NOX2 increased and transcription factor Nrf2 that decreased ROS were induced after TBI. The combination therapy (NOX inhibitor apocynin + Nrf2 activator TBHQ) improved cognitive dysfunction in TBI [ 116 ]. Di Filippo et al, found that multiple-sclerosis-associated cognitive dysfunction was caused by synaptic dysfunction via a long-term potentiation (LTP) blockade mediated by NOX2 [ 120 ].…”

Section: Association Of Nadph Oxidase In Cognitive Impairmentmentioning

confidence: 99%

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A Mini-Review of the NADPH Oxidases in Vascular Dementia: Correlation with NOXs and Risk Factors for VaD

Choi

Lee

2017

IJMS

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Oxidative stress (OS) is one of the factors that cause dementia conditions such as Alzheimer’s disease and vascular dementia (VaD). In the pathogenesis of VaD, OS is associated with risk factors that include increased age, hypertension, and stroke. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are a molecular source of reactive oxygen species (ROS). According to recent studies, inhibition of NOX activity can reduce cognitive impairment in animal models of VaD. In this article, we review the evidence linking cognitive impairment with NOX-dependent OS, including the vascular NOX and non-vascular NOX systems, in VaD.

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“…Nuclear factor erythroid 2‐related factor 2, a classical cytoprotective transcription factor, has been reported to impart protective effects against oxidative injury . Nrf‐2 is combined with its inhibitor Keap‐1 as a heterodimer in the cytoplasm under normal conditions .…”

Section: Introductionmentioning

confidence: 99%

Protective effects of leonurine against ischemic stroke in mice by activating nuclear factor erythroid 2‐related factor 2 pathway

Xie

Zhang

et al. 2019

CNS Neurosci Ther

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Aims Leonurine has been shown to trigger antioxidant responses during ischemic stroke, and nuclear factor erythroid 2‐related factor 2 (Nrf‐2) imparts protective effects against oxidative injury. The present study has determined that leonurine prevents ischemic injury of brain tissues via Nrf‐2 pathway activation. Methods Male ICR mice and Nrf‐2−/− mice were subjected to permanent middle cerebral artery occlusion (pMCAO) and received leonurine treatment at 2 hours after pMCAO by intraperitoneal injection. Neurological deficit scores as well as infarct volume were assessed to determine the neuroprotective role of leonurine. Nrf‐2 was investigated using Western blotting and real‐time polymerase chain reaction (RT‐PCR) analysis to elucidate the neuroprotective mechanism of leonurine. Commercial kits were employed to determine reactive oxygen species (ROS), superoxide (SOD), catalase (CAT), glutathione peroxidase (GSH‐Px), malonaldehyde (MDA), and glutathione (GSH). Vascular endothelial growth factor (VEGF) was evaluated by Western blotting and RT‐PCR analysis, and VEGF was localized using immunofluorescence. Results The application of leonurine on ICR mice resulted in an improvement in neurological deficit scores and a reduction in infarct volume. Leonurine upregulated nuclear Nrf‐2 protein and increased total Nrf‐2 protein expression and mRNA levels. Leonurine regulated SOD, MDA, CAT, GSH, and GSH‐Px, and it significantly inhibited ROS production in ICR mice. Leonurine improved VEGF expression and increased VEGF expression in neurons, astrocytes, and endothelial cells. However, leonurine had no obvious beneficial effects on Nrf‐2−/− mice. Conclusions Leonurine exerted neuroprotective effects, promoted antioxidant responses, and upregulated VEGF expression by activating the Nrf‐2 pathway.

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A combination antioxidant therapy to inhibit NOX2 and activate Nrf2 decreases secondary brain damage and improves functional recovery after traumatic brain injury

Cited by 63 publications

References 68 publications

The microRNA miR-7a-5p ameliorates ischemic brain damage by repressing α-synuclein

The microRNA miR-7a-5p ameliorates ischemic brain damage by repressing α-synuclein

A Mini-Review of the NADPH Oxidases in Vascular Dementia: Correlation with NOXs and Risk Factors for VaD

Protective effects of leonurine against ischemic stroke in mice by activating nuclear factor erythroid 2‐related factor 2 pathway

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