Nrf2 Deficiency Exacerbates Cognitive Impairment and Reactive Microgliosis in a Lipopolysaccharide-Induced Neuroinflammatory Mouse Model (original) (raw)
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NRF2-regulation in brain health and disease: Implication of cerebral inflammation
Neuropharmacology, 2014
The nuclear factor erythroid 2 related factor 2 (NRF2) is a key regulator of endogenous inducible defense systems in the body. Under physiological conditions NRF2 is mainly located in the cytoplasm. However, in response to oxidative stress, NRF2 translocates to the nucleus and binds to specific DNA sites termed "anti-oxidant response elements" or "electrophile response elements" to initiate transcription of cytoprotective genes. Acute oxidative stress to the brain, such as stroke and traumatic brain injury is increased in animals that are deficient in NRF2. Insufficient NRF2 activation in humans has been linked to chronic diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis.
Journal of Neuroinflammation, 2020
Background Chronic cerebral hypoperfusion causes damage to the brain’s white matter underpinning vascular cognitive impairment. Inflammation and oxidative stress have been proposed as key pathophysiological mechanisms of which the transcription factor Nrf2 is a master regulator. We hypothesised that white matter pathology, microgliosis, blood-brain barrier breakdown and behavioural deficits induced by chronic hypoperfusion would be exacerbated in mice deficient in the transcription factor Nrf2. Methods Mice deficient in Nrf2 (male heterozygote or homozygous for Nrf2 knockout) or wild-type littermates on a C57Bl6/J background underwent bilateral carotid artery stenosis (BCAS) to induce chronic cerebral hypoperfusion or sham surgery and survived for a further 6 weeks. White matter pathology was assessed with MAG immunohistochemistry as a marker of altered axon-glial integrity; alterations to astrocytes and microglia/macrophages were assessed with GFAP and Iba1 immunohistochemistry, an...
The role of Nrf2 signaling in counteracting neurodegenerative diseases
FEBS Journal, 2018
The transcription factor Nrf2 (nuclear factor-erythroid 2 p45-related factor 2) functions at the interface of cellular redox and intermediary metabolism. Nrf2 target genes encode antioxidant enzymes, and proteins involved in xenobiotic detoxification, repair and removal of damaged proteins and organelles, inflammation, and mitochondrial bioenergetics. The function of Nrf2 is altered in many neurodegenerative disorders, such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Friedreich's ataxia. Nrf2 activation mitigates multiple pathogenic processes involved in these neurodegenerative disorders through upregulation of antioxidant defenses, inhibition of inflammation, improvement of mitochondrial function, and maintenance of protein homeostasis. Small molecule pharmacological activators of Nrf2 have shown protective effects in numerous animal models of neurodegenerative diseases, and in cultures of human cells expressing mutant proteins. Targeting Nrf2 signaling may provide a therapeutic option to delay onset, slow progression, and ameliorate symptoms of neurodegenerative disorders.
Nrf2 Signaling: An Adaptive Response Pathway for Neurodegenerative Disorders
A Master Regulator of Oxidative Stress - The Transcription Factor Nrf2, 2016
Oxidative damage contributes to pathogenesis in many neurodegenerative diseases. As the indicator and regulator of oxidative stress, the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway has been shown to have dynamic changes and examined for its neuroprotective role in many cases. Nrf2 is emerging as a regulatory protein in neuronal death, since it helps neuronal cells to meet with oxidative insults. In this chapter, we summarize the role of Nrf2 as a master regulator of oxidative stress. Furthermore, we treat some natural and chemical substances able to modulate the Nrf2 pathway and, therefore, their possible use in the neurodegenerative diseases therapeutic treatment.
Nrf2-Mediated Signaling as a Therapeutic Target in Alzheimer’s Disease
The Open neurology journal, 2024
Nrf2 is a major transcriptional factor that controls gene expression in normal health and pathological conditions. It regulates and controls the manifestation of various major elements of oxidative stress, neuro-inflammation, autophagy, and mitochondrial bioenergetics in the centre and periphery. Besides, Nrf2 activity is also controlled at various stages, such as protein degradation, transcription, and post-translation. Growing evidence suggests changes in the levels of Nrf2 in degenerative disorders, such as Alzheimer's disease (AD). AD is characterised by elevated oxidative stress, neuro-inflammation, synaptic dysfunction, and proteinopathies, which lead to the progressive loss of memory. A decrease in the expression of Nrf2 and its downstream target genes was identified in AD. Recent studies have shown that Nrf2 interferes with various main pathogenic processes in AD, including amyloid and tau pathologies. The current review focuses on brief in the regulation of Nrf2 and the association of Nrf2 with AD, along with the currently available Nrf2 activators.
Cerebrovascular and Neurological Disorders: Protective Role of NRF2
International Journal of Molecular Sciences, 2019
Cellular defense mechanisms, intracellular signaling, and physiological functions are regulated by electrophiles and reactive oxygen species (ROS). Recent works strongly considered imbalanced ROS and electrophile overabundance as the leading cause of cellular and tissue damage, whereas oxidative stress (OS) plays a crucial role for the onset and progression of major cerebrovascular and neurodegenerative pathologies. These include Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), stroke, and aging. Nuclear factor erythroid 2-related factor (NRF2) is the major modulator of the xenobiotic-activated receptor (XAR) and is accountable for activating the antioxidative response elements (ARE)-pathway modulating the detoxification and antioxidative responses of the cells. NRF2 activity, however, is also implicated in carcinogenesis protection, stem cells regulation, anti-inflammation, anti-aging, and so forth. Herein, we brief...
NRF2 as a Therapeutic Target in Neurodegenerative Diseases
ASN Neuro
Increased reactive oxygen species production and oxidative stress have been implicated in the pathogenesis of numerous neurodegenerative conditions including among others Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedrich's ataxia, multiple sclerosis, and stroke. The endogenous antioxidant response pathway protects cells from oxidative stress by increasing the expression of cytoprotective enzymes and is regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). In addition to regulating the expression of antioxidant genes, NRF2 has also been shown to exert anti-inflammatory effects and modulate both mitochondrial function and biogenesis. This is because mitochondrial dysfunction and neuroinflammation are features of many neurodegenerative diseases as well NRF2 has emerged as a promising therapeutic target. Here, we review evidence for a beneficial role of NRF2 in neurodegenerative conditions and the potential of specific NRF2 activators as therapeutic agents.