Nrf2–ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases

Buendía, Izaskun; Michalska, Patrycja; Navarro, Elisa; Gameiro, Isabel; Egea, Javier; León, Rafael

doi:10.1016/j.pharmthera.2015.11.003

Cited by 526 publications

(352 citation statements)

References 318 publications

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“…Stroke and traumatic brain injury (TBI) involve glial and peripheral immune cell activation at the site of injury that varies as the injury progresses. This extensive neuroinflammation and oxidative stress is consistent with elevated NF-κB activity concomitant with impaired Nrf2 activity [10,11], hence there is abundant evidence for inverse regulation of Nrf2 and NF-κB in neurodegenerative disease. Indeed, Nrf2 expression is diminished in human post-mortem tissue of AD and ALS patients [12,13].…”

Section: Inverse Regulation Of Nrf2 and Nf-κb In Neurodegenerationmentioning

confidence: 70%

Interplay between Nrf2 and NF-κB in Neuroinflammatory Diseases

Liddell¹

2017

J Clin Cell Immunol

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Many neurodegenerative conditions involve redox imbalance and neuroinflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB) are key transcription factors regulating antioxidant and inflammatory pathways, respectively. These two opposing factors are inversely regulated, with activity of one most often accompanied by diminished activity of the other, giving rise to the oxidative stress and neuroinflammation evident in neurodegeneration. Emerging evidence is uncovering a complex interplay between Nrf2 and NF-κB, involving extensive interaction of regulatory mechanisms including cytosolic activators and repressors, transactivation partners and direct transcriptional crosstalk. Understanding these interactions may provide insight into the pathophysiology of neuroinflammatory diseases and facilitate discovery of novel therapeutic targets. Keywords Nrf2 Function and ActivationNrf2 is the master regulator of antioxidant pathways, responsible for promoting the transcription of hundreds of antioxidant and cytoprotective genes, and in the brain appears to be repressed in neurons and predominantly restricted to glia [1,2]. Nrf2 is a cap'n' collar basic leucine zipper transcription factor. Under normal conditions, Nrf2 is bound in the cytosol by its negative regulator Kelch-like ECHassociated protein (Keap1), a substrate adaptor protein of a Cullin3-dependent ubiquitin E3 ligase complex. Keap1 constitutively targets Nrf2 for proteasomal degradation. When activated, Nrf2 dissociates from Keap1 and can translocate to the nucleus where it forms heterodimers with small Maf proteins and binds to antioxidant response elements (AREs), promoting the transcription of a battery of antioxidant and cytoprotective genes [3]. Nrf2 targets include genes for glutathione synthesis and utilization (e.g. GCLM, GCLC, GSTs), the thioredoxin and peroxiredoxin systems, NAPDH generation, iron metabolism (HMOX1, FTL, FTH) and quinone detoxification (NQO1) [4]. Nrf2 can be activated in response to oxidative stress and electrophiles via Keap1. Keap1 contains several highly sensitive cysteine residues that when oxidised cause Nrf2 to dissociate from Keap1, allowing Nrf2 to translocate to the nucleus. Thus Keap1 acts as a redox sensor [3]. Nrf2 activity is also regulated by kinases such as GSK3β [5]. Regulation of NF-κB ActivationNF-κB is a key regulator of the cellular inflammatory profile, promoting the transcription of inflammatory genes. In the brain, NF-κB signalling occurs predominantly in microglia, as well as astrocytes and oligodendrocytes, but not in neurons [6]. The NF-κB complex consists of homo-or heterodimers of p65, RelB, c-Rel, p50 and p52, the most abundant of which is p65/p50. The dimers are bound in the cytosol by a family of repressor proteins called inhibitor of κB (IκB), which include IκBα, IκBβ, IκBε, IκBγ and Bcl-3. IκB is phosphorylated by the IκB kinase (IKK) complex, consisting of IKKα, IKKβ and IKKγ subunits [7]. Upon activation by stimuli including TNFα, LPS and IL-1, IKK phosph...

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Section: Inverse Regulation Of Nrf2 and Nf-κb In Neurodegenerationmentioning

confidence: 70%

Interplay between Nrf2 and NF-κB in Neuroinflammatory Diseases

Liddell¹

2017

J Clin Cell Immunol

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“…Aging is the main risk factor for neurodegeneration and is associated with enhanced ROS/RNS levels and lower antioxidant capacity. Consistently, deregulation of Nrf2 pathway has been linked with aging, as well as with an enhanced susceptibility to and/or accelerated progression of neurodegenerative diseases [99][100][101].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 84%

Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

Paladino

Conte

Caggiano

et al. 2018

Cell Physiol Biochem

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A general hallmark of neurological diseases is the loss of redox homeostasis that triggers oxidative damages to biomolecules compromising neuronal function. Under physiological conditions the steady-state concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are finely regulated for proper cellular functions. Reduced surveillance of endogenous antioxidant defenses and/or increased ROS/RNS production leads to oxidative stress with consequent alteration of physiological processes. Neuronal cells are particularly susceptible to ROS/RNS due to their biochemical composition. Overwhelming evidences indicate that nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-linked pathways are involved in protective mechanisms against oxidative stress by regulating antioxidant and phase II detoxifying genes. As such, Nrf2 deregulation has been linked to both aging and pathogenesis of many human chronic diseases, including neurodegenerative ones such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis. Nrf2 activity is tightly regulated by a fine balance between positive and negative modulators. A better understanding of the regulatory mechanisms underlying Nrf2 activity could help to develop novel therapeutic interventions to prevent, slow down or possibly reverse various pathological states. To this end, microRNAs (miRs) are attractive candidates because they are linked to intracellular redox status being regulated and, post-transcriptionally, regulating key components of ROS/RNS pathways, including Nrf2.

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“…Nrf2 activators demonstrated activity in in vitro and in vivo in different neurodegenerative mouse models, protecting neurons, decreasing the accumulation of aberrant proteins and increasing life span (Buendia et al, 2016; Joshi and Johnson 2012). The existing data are strongest for PD, ALS, and multiple sclerosis models, but the therapeutic potential of this pathway in AD and HD is under investigation.…”

Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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Nrf2–ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases

Cited by 526 publications

References 318 publications

Interplay between Nrf2 and NF-κB in Neuroinflammatory Diseases

Interplay between Nrf2 and NF-κB in Neuroinflammatory Diseases

Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

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