Nrf2/ARE Signaling Pathway: Key Mediator in Oxidative Stress and Potential Therapeutic Target in ALS

Petri, Susanne; Körner, Sonja; Kiaei, Mahmoud

doi:10.1155/2012/878030

Cited by 162 publications

(136 citation statements)

References 53 publications

(53 reference statements)

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“…Nrf2 works by binding to the antioxidant response element (ARE) and consequently regulating various genes which are responsible for anti-oxidative, antiinflammatory and mitochondrial protection actions. Coenzyme Q10, superoxide dismutase, quinone oxidorectuse, and glutathione-S-transferase, heme oxygenase-1 are some of the ARE-containing gene promoters [53,54]. These protective genes are activated in response to Nrf2 which ultimately leads to maintenance of redox balance in the body.…”

Section: Discussionmentioning

confidence: 99%

Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2–ARE pathway

et al. 2018

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Objective: The objectives of our study were to investigate the possible effect of rosuvastatin in ameliorating high salt and cholesterol diet (HSCD)-induced cognitive impairment and to also investigate its possible action via the Nrf2-ARE pathway. Methods: In silico studies were performed to check the theoretical binding of rosuvastatin to the Nrf2 target. HSCD was used to induce cognitive impairment in rats and neurobehavioral studies were performed to evaluate the efficacy of rosuvastatin in enhancing cognition. Biochemical analyses were used to estimate changes in oxidative markers. Western blot and immunohistochemical analyses were done to check Nrf2 translocation. TUNEL and caspase 3 tests were performed to evaluate reversal of apoptosis by rosuvastatin. Results: Rosuvastatin showed good theoretical affinity to Nrf2, significantly reversed changes in oxidative biomarkers which were induced by HSCD, and also improved the performance of rats in the neurobehavioral test. A rise in nuclear translocation of Nrf2 was revealed through immunohistochemical analysis and western blot. TUNEL staining and caspase 3 activity showed attenuation of apoptosis. Discussion: We have investigated a novel mechanism of action for rosuvastatin (via the Nrf2-ARE pathway) and demonstrated that it has the potential to be used in the treatment of cognitive impairment. KEYWORDSCognitive impairment; rosuvastatin; high-salt and cholesterol diet; oxidative stress; Nrf2; nuclear factor (erythroid-derived 2)-like 2

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Section: Discussionmentioning

confidence: 99%

Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2–ARE pathway

et al. 2018

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“…However, the magnitude of the changes, particularly at the symptomatic stage, is greater in double transgenic mice than in SOD1 mice. The decrease in Nrf2, which regulates cellular antioxidant responses [60] in double transgenic mice compared to SOD1 mice, is particularly noteworthy as potentially part of ALS pathogenesis. Previous studies have reported decreased Nrf2 expression in postmortem brain and spinal cord tissues from sporadic ALS patients [61] and in SOD1(G93A) motor neurons [62].…”

Section: Discussionmentioning

confidence: 99%

H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Nandar

Neely

Simmons

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Keywords:H63D HFE SOD1(G93A) ALS Iron Oxidative stress Gliosis H63D HFE is associated with iron dyshomeostasis and oxidative stress; each of which plays an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. To examine the role of H63D HFE in ALS, we generated a double transgenic mouse line (SOD1/H67D) carrying the H67D HFE (homologue of human H63D) and SOD1(G93A) mutations. We found double transgenic mice have shorter survival and accelerated disease progression. We examined parameters in the lumbar spinal cord of double transgenic mice at 90 days (presymptomatic), 110 days (symptomatic) and end-stage. Transferrin receptor and L-ferritin expression, both indicators of iron status, were altered in double transgenic and SOD1 mice starting at 90 days, indicating loss of iron homeostasis in these mice. However, double transgenic mice had higher L-ferritin expression than SOD1 mice. Double transgenic mice exhibited increased Iba-1 immunoreactivity and caspase-3 levels, indicating increased microglial activation which would be consistent with the higher L-ferritin levels. Although both SOD1 and double transgenic mice had increased GFAP expression, the magnitude of the increase was higher in double transgenic mice at 110 days, suggesting increased gliosis in these mice. Increased hemeoxygenase-1 and decreased nuclear factor E2-related factor 2 levels in double transgenic mice strongly suggest the accelerated disease process could be associated with increased oxidative stress. There was no evidence of TAR-DNA-binding protein 43 mislocalization to the cytoplasm in double transgenic mice; however, there was evidence suggesting neurofilament disruption, which has been reported in ALS. Our findings indicate H63D HFE modifies ALS pathophysiology via pathways involving oxidative stress, gliosis and disruption of cellular functions.

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“…Recently, Nrf-2 activation was observed in humans in settings of chronic diseases such as PD (30,32,37), Alzheimer's disease (14), and amyotrophic lateral sclerosis (52). Brennan et al showed that DMF, by acting as an electrophile, modulates specific KEAP1 cysteine residues and exerts more robust allosteric conformational changes-leading to a diminished KEAP1-dependent degradation of Nrf-2 (10).…”

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confidence: 99%

The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

Campolo

Casili

Biundo

et al. 2017

Antioxidants & Redox Signaling

121

101

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Aim: Oxidative stress plays a key role in Parkinson disease (PD), and nuclear transcription factor related to NF-E2 (Nrf-2) is involved in neuroprotection against PD. The aim of the present study was to investigate a role for nuclear factor-jB (NF-jB)/Nrf-2 in the neurotherapeutic action of dimethyl fumarate (DMF) in a mouse model of PD and in vitro in SHSY-5Y cells. Results: Daily oral gavage of DMF (10, 30, and 100 mg/kg) significantly reduced neuronal cell degeneration of the dopaminergic tract and behavioral impairments induced by four injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Moreover, treatment with DMF prevented dopamine depletion, increased tyrosine hydroxylase and dopamine transporter activities, and also reduced the number of a-synucleinpositive neurons. Furthermore, DMF treatment upregulated the Nrf-2 pathway, increased NeuN + /Nrf-2 + cell number in the striatum, induced activation of manganese superoxide dismutase and heme oxygenase-1, and regulated glutathione levels. Moreover, DMF reduced interleukin 1 levels, cyclooxygenase 2 activity, and nitrotyrosine neuronal nitrite oxide synthase expression. This treatment also modulated microglia activation, restored nerve growth factor levels, and preserved microtubule-associated protein 2 alterations. The protective effects of DMF treatment, via Nrf-2, were confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline.Innovation: These findings demonstrate that DMF, both in a mouse model of PD and in vitro, provides, via regulation of the NF-jB/Nrf-2 pathway, novel cytoprotective modalities that further augment the natural antioxidant response in neurodegenerative and inflammatory disease models. Conclusion: These results support the thesis that DMF may constitute a promising therapeutic target for the treatment of PD. Antioxid. Redox Signal. 27, 453-471.

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Nrf2/ARE Signaling Pathway: Key Mediator in Oxidative Stress and Potential Therapeutic Target in ALS

Cited by 162 publications

References 53 publications

Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2–ARE pathway

Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2–ARE pathway

H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

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