Mild oxidative stress activates Nrf2 in astrocytes, which contributes to neuroprotective ischemic preconditioning

Bell, Karen; Al-Mubarak, Bashayer; Fowler, Jill H.; Baxter, Paul; Gupta, Kunal; Tsujita, Teppei; Chowdhry, Sudhir; Patani, Rickie; Chandran, Siddharthan; Horsburgh, Karen; Hayes, John D.; Hardingham, Giles E.

doi:10.1073/pnas.1015229108

Cited by 121 publications

(129 citation statements)

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“…Elevated Nrf2 activity in astrocytes protects neurons both in vitro (7,8) and in vivo (9,10), and has been shown to contribute to the neuroprotective effect of ischemic preconditioning (23). Through the regulatory mechanism we uncovered, the level of Nrf2 activity in a perisynaptic astrocyte is matched to the degree of activity in the adjacent synapse (Fig.…”

Section: Discussionmentioning

confidence: 97%

Neuronal activity regulates astrocytic Nrf2 signaling

Habas

Hahn

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear factor erythroid 2-related factor 2 (Nrf2), the transcriptional master regulator of the stress-induced antioxidant response, plays a key role in neuronal resistance to oxidative stress and glutamateinduced excitotoxicity. Nrf2-mediated neuroprotection is primarily conferred by astrocytes both in vitro and in vivo, but little is known about physiologic signals that regulate neuronal and astrocytic Nrf2 signaling. Here, we report that activity of the Nrf2 pathway in the brain is fine-tuned through a regulatory loop between neurons and astrocytes: elevated neuronal activity leads to secretion of glutamate and other soluble factors, which activate the astrocytic Nrf2 pathway through a signaling cascade that involves group I metabotropic glutamate receptors and intracellular Ca 2+ . Therefore, regulation of endogenous antioxidant signaling is one of the functions of the neuron-astrocyte tripartite synapse; by matching the astrocyte neuroprotective capacity to the degree of activity in adjacent neuronal synapses, this regulatory mechanism may limit the physiologic costs associated with Nrf2 activation.

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Section: Discussionmentioning

confidence: 97%

Neuronal activity regulates astrocytic Nrf2 signaling

Habas

Hahn

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Our data therefore support a critical role for PKCδ in astrocyte Nrf2-mediated antioxidant response, as it would coordinate a permissive Nrf2-S40 phosphorylation, with an active p35/ Cdk5-mediated Nrf2-T395/S433/T439 phosphorylation. Whether this Cdk5-Nrf2 transduction pathway accounts for neuroprotection during ischemic preconditioning 18 is a tempting possibility yet to be determined. However, the fact that ischemic preconditioning may be dependent on astrocyte Nrf2 transcriptional activity 18 strongly supports this notion.…”

Section: Discussionmentioning

confidence: 99%

“…Whether this Cdk5-Nrf2 transduction pathway accounts for neuroprotection during ischemic preconditioning 18 is a tempting possibility yet to be determined. However, the fact that ischemic preconditioning may be dependent on astrocyte Nrf2 transcriptional activity 18 strongly supports this notion. Our results also support the notion that astrocytes are active players in neurotransmission.…”

Section: Discussionmentioning

confidence: 99%

“…13 However, whether Nrf2 has a function in astrocyte-mediated neuronal protection is a matter of debate. [14][15][16][17][18] Like postsynaptic neurons, astrocytes express ionotropic glutamate-receptor subtype NMDAR, 19 although their precise function in these glial cells is still enigmatic. In view that excess NMDAR activity, by inhibiting APC/C-Cdh1 in neurons, 6 leads to oxidative damage, 7 we sought to investigate whether astrocyte NMDAR, by sensing neurotransmission, would support neuronal survival.…”

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confidence: 99%

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Astrocyte NMDA receptors' activity sustains neuronal survival through a Cdk5–Nrf2 pathway

et al. 2015

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Neurotransmission unavoidably increases mitochondrial reactive oxygen species. However, the intrinsic antioxidant defense of neurons is weak and hence the mechanism whereby these cells are physiologically protected against oxidative damage is unknown. Here we found that the antioxidant defense of neurons is repressed owing to the continuous protein destabilization of the master antioxidant transcriptional activator, nuclear factor-erythroid 2-related factor-2 (Nrf2). By contrast, Nrf2 is highly stable in neighbor astrocytes explaining their robust antioxidant defense and resistance against oxidative stress. We also show that subtle and persistent stimulation of N-methyl-D-aspartate receptors (NMDAR) in astrocytes, through a mechanism not requiring extracellular Ca 2+ influx, upregulates a signal transduction pathway involving phospholipase C-mediated endoplasmic reticulum release of Ca 2+ and protein kinase Cδ activation. Active protein kinase Cδ promotes, by phosphorylation, the stabilization of p35, a cyclin-dependent kinase-5 (Cdk5) cofactor. Active p35/Cdk5 complex in the cytosol phosphorylates Nrf2 at Thr 395 , Ser 433 and Thr 439 that is sufficient to promote Nrf2 translocation to the nucleus and induce the expression of antioxidant genes. Furthermore, this Cdk5-Nrf2 transduction pathway boosts glutathione metabolism in astrocytes efficiently protecting closely spaced neurons against oxidative damage. Thus, intercellular communication through NMDAR couples neurotransmission with neuronal survival.

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“…This implies that the increased HO-1 expression by EPS may lead to excessive free iron accumulation and subsequently ROS production in the intracellular milieu. In addition, because mild oxidative stress activates the Nrf2 pathway, 39) it is assumed that EPS has the potential to induce oxidative stress. However, our results indicated that EPS failed to elevate ROS production (Fig.…”

Section: )mentioning

confidence: 99%

Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System

Yama

Sato

Murao

et al. 2016

Biological & Pharmaceutical Bulletin

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Heme oxygenase (HO)-1 has potent antioxidant and anti-inflammatory functions. Recent studies have shown that the upregulation of HO-1 is beneficial to counteract neuroinflammation, making HO-1 a new therapeutic target for neurological diseases. We have reported that epalrestat (EPS), which is currently used for the treatment of diabetic neuropathy, increases HO-1 levels through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in bovine aortic endothelial cells. In this study, we tested the hypothesis that EPS upregulates HO-1 via Nrf2 activation in the component cells of the nervous system, by using rat Schwann cells and human SH-SY5Y cells. Treatment of Schwann cells with EPS at near-plasma concentration led to a dramatic increase in HO-1 levels. Nrf2 knockdown by small interfering RNA (siRNA) suppressed the EPS-induced HO-1 expression. EPS did not promote the intracellular accumulation of free ferrous ion and reactive oxygen species, by increasing ferritin via Nrf2 during HO-1 induction. Moreover, EPS stimulated the expression of superoxide dismutase 1 and catalase, which also are Nrf2 target gene products. It also markedly increased HO-1 levels in SH-SY5Y cells through the activation of Nrf2. We demonstrated for the first time that EPS upregulates HO-1, superoxide dismutase, and catalase by activating Nrf2. We suggest that EPS has the potential to prevent several neurological diseases. Key words epalrestat; heme oxygenase (HO)-1; superoxide dismutase (SOD); catalaseHeme oxygenase (HO)-1 is a stress-responsive enzyme that has anti-inflammatory, antioxidant, and cytoprotective functions. Expectations are high that the regulation and amplification of HO-1 by pharmacological approaches would lead to the discovery of novel drugs for the treatment of a variety of diseases.1) HO-1 has emerged as an anti-inflammatory therapeutic target.2) In particular, targeting HO-1 in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, has been reported.3) As HO-1 expression is involved in neuropathological changes, its regulation is essential for the development of new therapeutic approaches.3) However, such metalloporphyrins as cobalt protoporphyrin IX, which are prototypical inducers of HO-1 and commonly used in experimental cell culture and animal models, are not applicable to clinical interventions because of their high toxicity.2) It is expected that the upregulation of HO-1 by currently available pharmacological agents, whose safety and pharmacokinetics have already been confirmed clinically, would be useful for the treatment of a variety of diseases.The biochemical activities of heme degradation products and their metabolic derivatives contribute to the cytoprotective function of HO-1. HO-1 catalyzes the degradation of heme to produce ferrous iron, carbon monoxide, and biliverdin, the latter of which is subsequently converted into bilirubin. Carbon monoxide is involved in inflammation regulation.4) Bilirubin and biliverdin, which can scavenge peroxyl radicals, are cytoprotec...

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Mild oxidative stress activates Nrf2 in astrocytes, which contributes to neuroprotective ischemic preconditioning

Cited by 121 publications

References 5 publications

Neuronal activity regulates astrocytic Nrf2 signaling

Neuronal activity regulates astrocytic Nrf2 signaling

Astrocyte NMDA receptors' activity sustains neuronal survival through a Cdk5–Nrf2 pathway

Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System

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