Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection

Zhang, Meijuan; Chen, An; Gao, Yanqin; Leak, Rehana K.; Chen, Jun; Zhang, Feng

doi:10.1016/j.pneurobio.2012.09.003

Cited by 499 publications

(379 citation statements)

References 212 publications

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“…HD is caused by cytosine-adenine-guanine triplet expansion, encoding additional glutamine residues in the protein huntingtin (Htt) [2] . HD patients exhibit abnormal body movements such as chorea, cognitive impairments and personality disorders [3] .…”

Section: Introductionmentioning

confidence: 99%

Protopanaxtriol protects against 3-nitropropionic acid-induced oxidative stress in a rat model of Huntington's disease

Gao

Chu

et al. 2015

Acta Pharmacol Sin

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Aim: Protopanaxtriol (Ppt) is extracted from Panax ginseng Mayer. In the present study, we investigated whether Ppt could protect against 3-nitropropionic acid (3-NP)-induced oxidative stress in a rat model of Huntington's disease (HD) and explored the mechanisms of action. Methods: Male SD rats were treated with 3-NP (20 mg/kg on d 1, and 15 mg/kg on d 2-5, ip). The rats received Ppt (5, 10, and 20 mg/kg, po) daily prior to 3-NP administration. Nimodipine (12 mg/kg, po) or N-acetyl cysteine (NAC, 100 mg/kg, po) was used as positive control drugs. The body weight and behavior were monitored within 5 d. Then the animals were sacrificed, neuronal damage in striatum was estimated using Nissl staining. Hsp70 expression was detected with immunohistochemistry. Reactive oxygen species (ROS) generation was measured using dihydroethidium (DHE) staining. The levels of components in the Nrf2 pathway were measured with immunohistochemistry and Western blotting. Results: 3-NP resulted in a marked reduction in the body weight and locomotion activity accompanied by progressive striatal dysfunction. In striatum, 3-NP caused ROS generation mainly in neurons rather than in astrocytes and induced Hsp70 expression. Administration of Ppt significantly alleviated 3-NP-induced changes of body weight and behavior, decreased ROS production and restored antioxidant enzymes activities in striatum. Moreover, Ppt directly scavenged free radicals, increased Nrf2 entering nucleus, and the expression of its downstream products heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidase 1 (NQO1) in striatum. Similar effects were obtained with the positive control drugs nimodipine or NAC. Conclusion: Ppt exerts a protective action against 3-NP-induced oxidative stress in the rat model of HD, which is associated with its anti-oxidant activity.

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Section: Introductionmentioning

confidence: 99%

Protopanaxtriol protects against 3-nitropropionic acid-induced oxidative stress in a rat model of Huntington's disease

Gao

Chu

et al. 2015

Acta Pharmacol Sin

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“…We have previously shown that CA induces NRF2 translocation to the nucleus where it binds to the antioxidant response element (ARE) consensus sequence in the promoter region of phase II genes, including glutamyl cysteine ligase modifier subunit (Gclm), glutamyl cysteine ligase catalytic subunit (Gclc), hemeoxygenase-1 (Hmox1, encoding HO-1), NADPH quinone oxidoreductase 1(Nqo1), ATP-dependent reductase, sulfiredoxin 1 (Srxn1), Na + -independent cystine-glutamate exchanger (Slc7a11, encoding xCT), and superoxide dismutase (Sod1/2/3) (45,46). Induction of these endogenous antiinflammatory and antioxidant genes is cytoprotective.…”

Section: Carnosic Acid Confers Neuroprotection In Vivo To Light-exposedmentioning

confidence: 99%

MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

Nagar

Noveral

Trudler

et al. 2017

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

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Gaining mechanistic insight into interaction between causative factors of complex multifactorial diseases involving photoreceptor damage might aid in devising effective therapies. Oxidative stress is one of the potential unifying mechanisms for interplay between genetic and environmental factors that contribute to photoreceptor pathology. Interestingly, the transcription factor myocyte enhancer factor 2d (MEF2D) is known to be important in photoreceptor survival, as knockout of this transcription factor results in loss of photoreceptors in mice. Here, using a mild light-induced retinal degeneration model, we show that the diminished MEF2D transcriptional activity in Mef2d +/− retina is further reduced under photostimulation-induced oxidative stress. Reactive oxygen species cause an aberrant redox modification on MEF2D, consequently inhibiting transcription of its downstream target, nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is a master regulator of phase II antiinflammatory and antioxidant gene expression. In the Mef2d heterozygous mouse retina, NRF2 is not up-regulated to a normal degree in the face of lightinduced oxidative stress, contributing to accelerated photoreceptor cell death. Furthermore, to combat this injury, we found that activation of the endogenous NRF2 pathway using proelectrophilic drugs rescues photoreceptors from photo-induced oxidative stress and may therefore represent a viable treatment for oxidative stress-induced photoreceptor degeneration, which is thought to contribute to some forms of retinitis pigmentosa and age-related macular degeneration.B lindness due to photoreceptor loss from a number of diseases is a prevalent and devastating condition in the human population. Genetic predisposition and environmental stress play major roles in the incidence and progression of the retinal degeneration. Understanding disease mechanisms and interactions of causative factors should help in the design of treatment strategies. Recent evidence indicates that oxidative stress, contributing to photoreceptor cell death, plays a significant role in the pathophysiology of nonsyndromic retinitis pigmentosa (RP) and possibly age-related macular degeneration (AMD) (1-3). Moreover, light-induced oxidative stress is known to potentiate photoreceptor loss in genetic models mimicking a number of human retinal degenerations (4-11).The oxidizing microenvironment of the retinal pigment epithelium (RPE)-photoreceptor complex has been predominantly attributed to high oxygen demand, abundant polyunsaturated fatty acids, and direct exposure to light, coupled with the adjacent choroidal hemodynamics (12). Light exposure compounded over many years in the presence of photosensitizers may prime photoreceptors and RPE for free radical/oxidative damage (12-14). In some animal models of photoreceptor degeneration, including RP and Leber congenital amaurosis, disease progression is accelerated by exposure to light and slowed by rearing in darkness (3, 15). Advanced age also compromises the endogenous antioxidant ...

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“…Nrf2 has been described as the "master regulator" of the antioxidant response, and it represents a molecular target with broad therapeutic potential [103]. Indeed, Nrf2 exerts a protective role in a number of neurodegenerative disease models [104]. Interestingly, Nrf2 has also been identified to be at the center of a network of over 250 coexpressed genes that were specifically altered in the hippocampi of animals with kainate-induced seizures [105].…”

Section: Nrf2 Pathwaymentioning

confidence: 99%

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

2014

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A major goal of contemporary epilepsy research is the identification of therapies to prevent the development of recurrent seizures in individuals at risk, including those with brain injuries, infections, or neoplasms; status epilepticus; cortical dysplasias; or genetic epilepsy susceptibility. In this review we consider the evidence largely from preclinical models for the antiepileptogenic activity of a diverse range of potential therapies, including some marketed antiseizure drugs, as well as agents that act by immune and inflammatory mechanisms; reduction of oxidative stress; activation of the mammalian target of rapamycin or peroxisome proliferatoractivated receptors γ pathways; effects on factors related to thrombolysis, hematopoesis, and angiogenesis; inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reducatase; brainderived neurotrophic factor signaling; and blockade of α2 adrenergic and cannabinoid receptors. Antiepileptogenesis refers to a therapy of which the beneficial action is to reduce seizure frequency or severity outlasting the treatment period. To date, clinical trials have failed to demonstrate that antiseizure drugs have such disease-modifying activity. However, studies in animal models with levetiracetam and ethosuximide are encouraging, and clinical trials with these agents are warranted. Other promising strategies are inhibition of interleukin 1β signaling by drugs such as VX-765; modulation of sphingosine 1-phosphate signaling by drugs such as fingolimod; activation of the mammalian target of rapamycin by drugs such as rapamycin; the hormone erythropoietin; and, paradoxically, drugs such as the α2 adrenergic receptor antagonist atipamezole and the CB1 cannabinoid antagonist SR141716A (rimonabant) with proexcitatory activity. These approaches could lead to a new paradigm in epilepsy drug therapy where treatment for a limited period prevents the occurrence of spontaneous seizures, thus avoiding lifelong commitment to symptomatic treatment.

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Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection

Cited by 499 publications

References 212 publications

Protopanaxtriol protects against 3-nitropropionic acid-induced oxidative stress in a rat model of Huntington's disease

Protopanaxtriol protects against 3-nitropropionic acid-induced oxidative stress in a rat model of Huntington's disease

MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

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