Targeting the Nrf2–Keap1 antioxidant defence pathway for neurovascular protection in stroke

Alfieri, Alessio; Srivastava, Salil; Siow, Richard; Modo, Michel; Fraser, Paul A.; Mann, Giovanni E.

doi:10.1113/jphysiol.2011.210294

Cited by 186 publications

(130 citation statements)

References 86 publications

(174 reference statements)

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“…Activation of oxidative/ inflammatory stress signaling cascades by drugs of abuse is the primary mechanism for increased endothelial activation and leukocyte migration across the BBB into the brain. Recent studies from our group (Sajja et al, 46 Naik et al, 115 and Prasad et al 146 ) and other groups (Alfieri et al 147 and Sandberg et al…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress

Sajja

Rahman

Cucullo

2015

J Cereb Blood Flow Metab

119

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Psychostimulants and nicotine are the most widely abused drugs with a detrimental impact on public health globally. While the long-term neurobehavioral deficits and synaptic perturbations are well documented with chronic use of methamphetamine, cocaine, and nicotine, emerging human and experimental studies also suggest an increasing incidence of neurovascular complications associated with drug abuse. Short-or long-term administration of psychostimulants or nicotine is known to disrupt blood-brain barrier (BBB) integrity/function, thus leading to an increased risk of brain edema and neuroinflammation. Various pathophysiological mechanisms have been proposed to underlie drug abuse-induced BBB dysfunction suggesting a central and unifying role for oxidative stress in BBB endothelium and perivascular cells. This review discusses drug-specific effects of methamphetamine, cocaine, and tobacco smoking on brain microvascular crisis and provides critical assessment of oxidative stress-dependent molecular pathways focal to the global compromise of BBB. Additionally, given the increased risk of human immunodeficiency virus (HIV) encephalitis in drug abusers, we have summarized the synergistic pathological impact of psychostimulants and HIV infection on BBB integrity with an emphasis on unifying role of endothelial oxidative stress. This mechanistic framework would guide further investigations on specific molecular pathways to accelerate therapeutic approaches for the prevention of neurovascular deficits by drugs of abuse.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress

Sajja

Rahman

Cucullo

2015

J Cereb Blood Flow Metab

119

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“…28,29 The results provide the first demonstration of miR-424 acting as a modulator of antioxidants after I/R by increasing the levels of MnSOD and EcSOD and stimulating MnSOD activity. Although SOD expression in the peri-infarct cortex was unaltered after 24 hours of reperfusion, MnSOD activity increased; in primary cortical neurons, MnSOD activity decreased after 6 hours of exposure to H 2 O 2 .…”

mentioning

confidence: 91%

MicroRNA-424 Protects Against Focal Cerebral Ischemia and Reperfusion Injury in Mice by Suppressing Oxidative Stress

Liu

Zhao

Wang

et al. 2015

Stroke

165

102

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513I schemic stroke is one of the leading causes of death and disability in the world, resulting from the disruption of blood supply to the brain. Intervention requires the restoration of blood flow, which can lead to reperfusion injury. Oxidative stress is thought to be the primary event during this process 1 because reperfusion stimulates an overproduction of reactive oxygen species (ROS), such as hydrogen peroxide (H 2 O 2 ), which leads to the oxidation of proteins, lipids, and DNA and can induce cell proliferation, growth arrest, apoptosis, and necrosis.2 Meanwhile, the dysfunction of superoxide dismutase (SOD) and glutathione peroxidase can compromise endogenous antioxidant defense mechanisms and further exacerbate oxidative stress and ischemic/reperfusion (I/R) injury.3,4 Nuclear factor erythroid 2-related factor (Nrf)2 activates the transcription of antioxidant stress genes whose products act concertedly to remove ROS through sequential enzymatic reactions. 5 Studies have uncovered the potential for Nrf2-mediated transcription to protect from neurodegeneration resulting from mechanisms involving oxidative stress. For this reason, Nrf2 is considered a valuable therapeutic target for free radical damage in brain after ischemia and reperfusion.MicroRNAs (miRs) are small (≈22 nt), noncoding, singlestranded RNA molecules that regulate gene expression at the posttranscriptional level by inhibiting translation or by cleaving RNA transcripts in a sequence-specific manner.6 MiR-424 is a tumor marker that is involved in cancer cell proliferation, Background and Purpose-We previously showed that the microRNA miR-424 protects against permanent cerebral ischemic injury in mice by suppressing microglia activation. This study investigated the role of miR-424 in transient cerebral ischemia in mice with a focus on oxidative stress-induced neuronal injury. Methods-Transient cerebral ischemia was induced in C57/BL6 mice by middle cerebral artery occlusion for 1 hour followed by reperfusion (ischemia/reperfusion). The miR-424 level in the peri-infarct cortex was quantified. Mice were also administered miR-424 angomir by intracerebroventricular injection. Cerebral infarct volume, neuronal apoptosis, and levels of oxidative stress markers and antioxidants were evaluated. In an in vitro experiment, primary cortical neurons were exposed to H 2 O 2 and treated with miR-424 angomir, nuclear factor erythroid 2-related factor 2 siRNA, and superoxide dismutase (SOD) inhibitor; cell activity, lactate dehydrogenase release, malondialdehyde level, and manganese (Mn)SOD activity were then evaluated. Results-MiR-424 levels in the peri-infarct cortex increased at 1 and 4 hours then decreased 24 hours after reperfusion.Treatment with miR-424 decreased infarct volume and inhibited neuronal apoptosis after ischemia/reperfusion, reduced reactive oxygen species and malondialdehyde levels in the cortex, and increased the expression and activation of MnSOD as well as the expression of extracellular SOD and the redox-sensitive transcription fact...

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“…The function of HO-1 is to catalyze heme to biliverdin, carbon monoxide and iron. It has been previously reported that Nrf-2 activation protects the neurons from ischemia (22). Under physiological conditions, Nrf2 is located in the cytosol and binds to Kelch-like ECH-associated protein 1 (Keap1).…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effects of lycopene pretreatment on transient global cerebral ischemia-reperfusion in rats: The role of the Nrf2/HO-1 signaling pathway

Lei

Zhang

et al. 2015

Molecular Medicine Reports

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Abstract. The present study aimed to investigate the neuroprotective effect of lycopene in a mouse model of bilateral common carotid artery occlusion (BCCAO) and the role of the Nrf2/HO-1 signaling pathway. A total of 60 male C57BL/6 mice, aged 12 weeks and weighing 20-24 g, were used in the present study. The mice were randomly assigned to three groups: Control, BCCAO and BCCAO + lycopene. The neurological score was assessed 24, 48 or 72 h following BCCAO. Hematoxylin and eosin staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were performed to detect neuronal death and survival. The production of glutathione (GSH) and reactive oxygen species were detected to investigate the oxidative stress. The expression levels of nuclear factor erythroid 2-related factor (Nrf2) and Heme oxygenase-1 (HO-1) were determined by western blotting. Lycopene significantly improved the neurological score in the BCCAO mice. It attenuated neuronal apoptosis, as indicated by TUNEL staining, and attenuated the oxidative stress induced by global ischemia. Lycopene increased the expression levels of Nrf2 and HO-1, indicating that the Nrf2/HO-1 signaling pathway may be involved in the neuroprotective effect of lycopene. The present study revealed that lycopene protects the brain from global ischemic injury, which is associated with its antiapoptotic effect and the activation of the Nrf2/HO-1 signaling pathway.

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Targeting the Nrf2–Keap1 antioxidant defence pathway for neurovascular protection in stroke

Cited by 186 publications

References 86 publications

Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress

Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress

MicroRNA-424 Protects Against Focal Cerebral Ischemia and Reperfusion Injury in Mice by Suppressing Oxidative Stress

Neuroprotective effects of lycopene pretreatment on transient global cerebral ischemia-reperfusion in rats: The role of the Nrf2/HO-1 signaling pathway

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