Therapeutic Potential of the Activators of the Nuclear Factor Erythroid 2-Related Factor 2–Antioxidant Response Element Pathway in Brain Disorders

Kume, Toshiaki

doi:10.1248/bpb.b17-00091

Cited by 9 publications

(4 citation statements)

References 30 publications

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“…One of the most studied antioxidant factors in the brain that directly regulates GSTs is the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2). Multiple studies have found that increasing Nrf2 activity can protect cells in the brain from oxidative stress [26]. Interestingly, there are multiple SNPs that were found in the promoter of Nrf2, and some of these polymorphisms led to reduced antioxidant response [27].…”

Section: Genetic Contributors To Brain Sensitivitymentioning

confidence: 99%

Time to get personal: A framework for personalized targeting of oxidative stress in neurotoxicity and neurodegenerative disease

Neal

Richardson

2018

Current Opinion in Toxicology

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The annual cost for neurological disorders in the United States was $789 billion in 2014, and with an aging population these numbers are expected to significantly increase in the next 50 years [1]. Neurodegenerative diseases make up a significant portion of these costs. Neurodegenerative diseases are characterized by the loss of neuronal populations in specific regions of the brain. Although the cause is still unknown for most of these diseases, both genetic and environmental factors are thought to play important roles. There are multiple convergent mechanisms underlying the unique susceptibility of neurons to degeneration, including aging, inflammation, mitochondrial dysfunction, and oxidative stress. Oxidative stress (OS) is of particular importance because evidence indicates that the neuronal populations lost in neurodegenerative diseases are particular susceptible to OS. OS is a complex neurotoxic mechanism that arises from excessive generation of free radicals such as reactive oxygen species (ROS), reduction in anti-oxidant factors, or a combination of the two. A complex interplay between the endogenous susceptibility of the brain, genetic factors, and environmental exposures leads to the harmful generation of OS in the brain and contributes significantly to the initiation and/or progression of neurodegeneration. Unfortunately, therapeutics for neurodegenerative diseases have consistently failed in clinical trials. Thus, a better understanding of the interplay between genetic susceptibility and common molecular mechanisms of environmental contributors to OS generation could aid in elucidation of novel therapeutic strategies for neurodegenerative diseases. This review will explore the current picture of oxidative stress in the brain as it relates to neurotoxicity, specifically exploring common mechanisms behind the endogenous susceptibility of the brain to OS, genetic susceptibility and environmental exposures leading to neurotoxicity, to identify precision/personalized medicine approaches for improving therapeutic outcome.

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Section: Genetic Contributors To Brain Sensitivitymentioning

confidence: 99%

Time to get personal: A framework for personalized targeting of oxidative stress in neurotoxicity and neurodegenerative disease

Neal

Richardson

2018

Current Opinion in Toxicology

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“…Nrf2 protects neurons by transcriptionally upregulating antioxidant enzyme genes that suppress oxidative stress. Several previous studies have demonstrated that oxidative stress, neuroinflammation, and neuronal injury can be prevented by increasing the activation of the Nrf2-related pathway [ 23 , 24 ]. The purpose of this study was to evaluate the effects of NXP032 on oxidative stress and cognitive dysfunction induced by aging by activating the Nrf2-ARE pathway.…”

Section: Introductionmentioning

confidence: 99%

NXP032 Ameliorates Aging-Induced Oxidative Stress and Cognitive Impairment in Mice through Activation of Nrf2 Signaling

2022

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Aging is a neurodegenerative disease that leads to cognitive impairment, and an increase in oxidative stress as a major cause is an important factor. It has been reported that aging-related cognitive impairment is associated with increased oxidative damage in several brain regions during aging. As a powerful antioxidant, vitamin C plays an important role in preventing oxidative stress, but due to its unstable chemical properties, it is easily oxidized and thus the activity of antioxidants is reduced. In order to overcome this easily oxidized vulnerability, we developed NXP032 (vitamin C/DNA aptamer complex) that can enhance the antioxidant efficacy of vitamin C using an aptamer. We developed NXP032 (vitamin C/DNA Aptamin C320 complex) that can enhance the antioxidant efficacy of vitamin C using an aptamer. In the present study, we evaluated the neuroprotective effects of NXP032 on aging-induced cognitive decline, oxidative stress, and neuronal damage in 17-month-old female mice. NXP032 was orally administered at 200 mg/kg of ascorbic acid and 4 mg/kg of DNA aptamer daily for eight weeks. Before the sacrifice, a cognitive behavioral test was performed. Administration of NXP032 alleviated cognitive impairment, neuronal damage, microglia activity, and oxidative stress due to aging. We found that although aging decreases the Nrf2-ARE pathway, NXP032 administration activates the Nrf2-ARE pathway to increase the expression of SOD-1 and GSTO1/2. The results suggest that the new aptamer complex NXP032 may be a therapeutic intervention to alleviate aging-induced cognitive impairment and oxidative stress.

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“…Stroke is a major cause of death and disability and ischemic stroke is the most widely recognized type of stroke. [1][2][3] Reperfusion of the blocked vessel is the standard treatment for patients diagnosed with ischemic stroke, but it may cause a cascade of secondary injuries. 4) The early inflammatory response to brain injury has great importance in the pathogenesis of ischemia/reperfusion (I/R) injury and this has produced enthusiasm for developing anti-inflammatory cures to combat I/R-caused damage.…”

Section: Introductionmentioning

confidence: 99%

Artesunate Provides Neuroprotection against Cerebral Ischemia–Reperfusion Injury <i>via</i> the TLR-4/NF-κB Pathway in Rats

Chen

Zhu

et al. 2021

Biological & Pharmaceutical Bulletin

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Inflammation has an important role in ischemia/reperfusion (I/R) injury. Artesunate (ART) has anti-microbial and anti-inflammatory pharmacological activities, and it is used for various types of serious malaria, including cerebral malaria. ART maintains a high concentration in the brain but little is known about the neuroprotective effect of ART against brain I/R injury. We studied the neuroprotection of ART against brain I/R injury and its underlying mechanism. In this study, rats were subjected to middle cerebral artery occlusion (MCAO) for 2 hours. After 24 hours of reperfusion, neurological deficits, cerebrum water content, infarct volume, HE-staining, MPO activity, and proinflammatory cytokine levels were measured. Administration of 20, 40, 80, and 160 mg/kg ART i.p. 10 min after MCAO significantly decreased brain water content and improved neurological deficits in a dose-dependent manner. A 80 mg/kg dosage was optimal. ART significantly reduced infarct volume, suppressed MPO activity and diminished the expressions of TLR-4, MyD88, NF-κB, TNF-α, and IL-6 in the area of the ischemic cortex. The neuroprotective action of ART against focal cerebral I/R injury might be due to the attenuation of inflammation through the TLR-4/NF-κB pathway.

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Therapeutic Potential of the Activators of the Nuclear Factor Erythroid 2-Related Factor 2–Antioxidant Response Element Pathway in Brain Disorders

Cited by 9 publications

References 30 publications

Time to get personal: A framework for personalized targeting of oxidative stress in neurotoxicity and neurodegenerative disease

Time to get personal: A framework for personalized targeting of oxidative stress in neurotoxicity and neurodegenerative disease

NXP032 Ameliorates Aging-Induced Oxidative Stress and Cognitive Impairment in Mice through Activation of Nrf2 Signaling

Artesunate Provides Neuroprotection against Cerebral Ischemia–Reperfusion Injury <i>via</i> the TLR-4/NF-κB Pathway in Rats

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