Critical Role of Nrf2 in Experimental Ischemic Stroke

Liu, Lei; Locascio, Logan M.; Doré, Sylvain

doi:10.3389/fphar.2019.00153

Cited by 116 publications

(113 citation statements)

References 215 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…24,28 Indeed, Nrf2/ARE signalling activation protects neurons against OGD/R-induced injury in vitro and cerebral ischaemia/reperfusion-induced injury in vivo. 46,47 In this study, we identified Nrf2/ARE signalling as the downstream target of the miR-148b-3p/Sestrin2 axis.…”

Section: Discussionmentioning

confidence: 87%

Inhibition of microRNA‐148b‐3p alleviates oxygen‐glucose deprivation/reoxygenation‐induced apoptosis and oxidative stress in HT22 hippocampal neuron via reinforcing Sestrin2/Nrf2 signalling

et al. 2020

Clin Exp Pharma Physio

View full text Add to dashboard Cite

MicroRNAs (miRNAs) have emerged as crucial regulators of neuronal injury during cerebral ischaemia/reperfusion injury. Various miRNAs are dysregulated during this pathological process; however, the precise role of these miRNAs in regulating neuronal injury remains largely unknown. In the current study, we explored the potential function of microRNA‐148b‐3p (miR‐148b‐3p) in regulating neuronal injury induced by oxygen‐glucose deprivation/reoxygenation (OGD/R) in vitro, a cellular model for mimicking cerebral ischaemia/reperfusion injury. We found that miR‐148b‐3p expression was significantly decreased in neurons in response to OGD/R exposure. Importantly, miR‐148b‐3p overexpression decreased cell viability and exacerbated apoptosis and reactive oxygen species (ROS) production in OGD/R‐exposed neurons. By contrast, miR‐148b‐3p inhibition improved cell viability and decreased apoptosis and ROS production in OGD/R‐exposed neurons. Notably, Sestrin2, a cytoprotective gene, was identified as a miR‐148b‐3p target gene. miR‐148b‐3p inhibition markedly increased Sestrin2 expression as well as the activation of nuclear factor erythroid‐2‐related factor 2 (Nrf2) antioxidant signalling. Moreover, silencing of Sestrin2 or Nrf2 significantly reversed the miR‐148‐3p‐inhibition‐mediated protective effect in OGD/R‐injured neurons. Overall, these results demonstrate that miR‐148b‐3p inhibition protects neurons from OGD/R‐induced apoptosis and ROS production through reinforcing Nrf2 antioxidant signalling via upregulation of Sestrin2. Our study indicates that the miR‐148b‐3p/Sestrin2/Nrf2 axis plays an important role in regulating neuronal injury and may serve as a potential therapeutic target for providing neuroprotection during cerebral ischaemia/reperfusion injury.

show abstract

Section: Discussionmentioning

confidence: 87%

Inhibition of microRNA‐148b‐3p alleviates oxygen‐glucose deprivation/reoxygenation‐induced apoptosis and oxidative stress in HT22 hippocampal neuron via reinforcing Sestrin2/Nrf2 signalling

et al. 2020

Clin Exp Pharma Physio

View full text Add to dashboard Cite

show abstract

“…Nrf2 plays an indispensable role in maintaining cellular homeostasis. Substantial lines of evidence have suggested that it is bene cial for CNS diseases, including TBI [13][14][15]. Under physiologic conditions, Nrf2 binds with Keap1 in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury

Wang

Zhou²,

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Aucubin (Au), an iridoid glycoside from natural plants, has anti-oxidative and anti-inflammatory bioactivities; however, its effects on a traumatic brain injury (TBI) model remain unknown. We explored the potential role of Au in a H 2 O 2 -induced oxidant damage in primary cortical neurons and weight-drop induced-TBI in a mouse model. Methods: In vitro experiments, the various concentrations of Au (50 μg/ml, 100 μg/ml or 200 μg/ml) were added in culture medium at 0h and 6h after neurons stimulated by H 2 O 2 (100μM). After exposed for 12 hours, neurons were collected for western blot (WB), immunofluorescence and M29,79-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. In vivo experiments, Au (20 mg/kg or 40 mg/kg) was administrated intraperitoneally at 30 min, 12 h, 24 h, and 48 h after modeling. Brain water content, neurological deficits and cognitive functions were measured at specific time, respectively. Cortical tissue around focal trauma was collected for WB, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, Nissl staining, quantitative real time polymerase chain reaction (q-PCR), immunofluorescence/immunohistochemistry and enzyme linked immunosorbent assay (ELISA) at 72 h after TBI. RNA interference experiments were performed to determine the effects of Nuclear factor erythroid-2 related factor 2 (Nrf2) on TBI mice with Au (40 mg/kg) treatment. Mice were intracerebroventricularly administrated with lentivirus at 72 h before TBI establishment. The cortex was obtained at 72 h after TBI and used for WB and q-PCR. Results: Au enhanced the translocation of Nrf2 into the nucleus, activated antioxidant enzymes, suppressed excessive generation of reactive oxygen species (ROS) and reduced cell apoptosis both in vitro and vivo experiments. In the mice model of TBI, Au markedly attenuated brain edema, histological damages and improved neurological and cognitive deficits. Au significantly suppressed high mobility group box 1(HMGB1)-mediated aseptic inflammation. Nrf2 knockdown in TBI mice blunted the antioxidant and anti-inflammatory neuroprotective effects of the Au. Conclusions: Taken together, our data suggest that Au provides a neuroprotective effect in TBI mice model by inhibiting oxidative stress and inflammatory responses; the mechanisms involve triggering Nrf2-induced antioxidant system.

show abstract

“…Majority of studies supported the upregulation of Nrf2 after cerebral ischemia, while some studies indicated suppression of Nrf2. These discrepancies might be due to different experimental factors such as animal strain, age, animal model, et al (Liu et al., 2019) Multiple evidence supporting the neuroprotective effect of Nrf2 against ischemia was obtained from Nrf2 knockout (Nrf2 −/− ) mice. Nrf2 knockout mice showed exacerbated brain damage and neurological deficits after ischemic stroke compared with the wild‐type controls (Liu et al., 2019).…”

Section: Discussionmentioning

confidence: 99%

“…These discrepancies might be due to different experimental factors such as animal strain, age, animal model, et al (Liu et al., 2019) Multiple evidence supporting the neuroprotective effect of Nrf2 against ischemia was obtained from Nrf2 knockout (Nrf2 −/− ) mice. Nrf2 knockout mice showed exacerbated brain damage and neurological deficits after ischemic stroke compared with the wild‐type controls (Liu et al., 2019). Previous study showed that Nrf2 −/− mice are more sensitive to hyperoxic lung injury compared with wild‐type mice (Cho et al., 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Nrf2 −/− mice are more sensitive to hyperoxic lung injury compared with wild‐type mice (Cho et al., 2002). Activation of Nrf2 was found to reduce brain injury in rats subjected to cerebral ischemia (Alfieri et al., 2013) while Nrf2 −/− mice showed exacerbated brain damage after stroke (Liu, Locascio, & Doré, 2019). However, the effect of Nrf2 in neonatal HI brain injury has not been fully investigated.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Neuroprotective role of Nrf2 on hypoxic‐ischemic brain injury in neonatal mice

Zhang

Dou

Yang

2020

Synapse

View full text Add to dashboard Cite

Inflammation and oxidative stress play a key role in mediating the pathophysiology of hypoxic‐ischemic (HI) brain injury. Nrf2 is a transcriptional factor that contributes to the innate defense of the body against oxidative stress and inflammation. The current study investigated the effect of Nrf2 in neonatal HI brain injury using Nrf2−/− mice. Nrf2−/− and wild‐type Nrf2+/+ mice on a C57BL/6J background at postnatal day 9 underwent unilateral common carotid artery ligation, followed by hypoxia. Brain damage was determined by infarct size measurement. Apoptosis was evaluated by measuring the expression of Bax and Bcl‐2. The levels of inflammatory cytokines and mediators involved in oxidative stress were measured. Nrf2 knockout exacerbated HI injury‐induced brain infarct and cell apoptosis in the brain. Nrf2−/− mice showed increased inflammatory cytokines and MDA, and reduced activities of antioxidant enzymes including CAT, GSH‐Px, and SOD. Nrf2−/− mice showed reduced HO‐1 expression after HI injury compared with wild‐type mice. This study supported a protective effect of Nrf2 in neonatal HI brain injury.

show abstract

Critical Role of Nrf2 in Experimental Ischemic Stroke

Cited by 116 publications

References 215 publications

Inhibition of microRNA‐148b‐3p alleviates oxygen‐glucose deprivation/reoxygenation‐induced apoptosis and oxidative stress in HT22 hippocampal neuron via reinforcing Sestrin2/Nrf2 signalling

Inhibition of microRNA‐148b‐3p alleviates oxygen‐glucose deprivation/reoxygenation‐induced apoptosis and oxidative stress in HT22 hippocampal neuron via reinforcing Sestrin2/Nrf2 signalling

Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury

Neuroprotective role of Nrf2 on hypoxic‐ischemic brain injury in neonatal mice

Contact Info

Product

Resources

About