Inhibition of beta-amyloid-induced neurotoxicity by pinocembrin through Nrf2/HO-1 pathway in SH-SY5Y cells

Wang, Yumin; Miao, Yingchun; Mir, Aamina Zia; Cheng, Long; Wang, Lina; Zhao, Liman; Cui, Qifu; Zhao, Weili; Wang, Hongquan

doi:10.1016/j.jns.2016.07.010

Cited by 81 publications

(35 citation statements)

References 41 publications

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“…Bar, 25 μm in all images. Quantitation of the cytoplasmic SOD-1 and HO-1 fluorescent signals is shown in Additional file 3: Figure S3 alterations in mitochondrial respiration and ATP production both in neuronal cultures and transgenic mouse models [97][98][99][100][101][102]. In spite of their potential for the development of future therapeutic strategies, the consequences of the prolonged use of Nrf2 activators should be further explored, specially taking into consideration the reported association of Nrf2 exacerbated activation with certain types of cancer [103].…”

Section: Discussionmentioning

confidence: 99%

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

2020

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Background: Mounting evidence points to a crucial role of amyloid-β (Aβ) in the pathophysiology of Alzheimer's disease (AD), a disorder in which brain glucose hypometabolism, downregulation of central elements of phosphorylation pathways, reduced ATP levels, and enhanced oxidative damage coexist, and sometimes precede, synaptic alterations and clinical manifestations. Since the brain has limited energy storage capacity, mitochondria play essential roles in maintaining the high levels of energy demand, but, as major consumers of oxygen, these organelles are also the most important generators of reactive oxygen species (ROS). Thus, it is not surprising that mitochondrial dysfunction is tightly linked to synaptic loss and AD pathophysiology. In spite of their relevance, the mechanistic links among ROS homeostasis, metabolic alterations, and cell bioenergetics, particularly in relation to Aβ, still remain elusive. Methods: We have used classic biochemical and immunocytochemical approaches together with the evaluation of real-time changes in global energy metabolism in a Seahorse Metabolic Analyzer to provide insights into the detrimental role of oligAβ in SH-SY5Y and primary neurons testing their pharmacologic protection by small molecules.Results: Our findings indicate that oligomeric Aβ induces a dramatic increase in ROS production and severely affects neuronal metabolism and bioenergetics. Assessment of global energy metabolism in real time demonstrated Aβ-mediated reduction in oxygen consumption affecting basal and maximal respiration and causing decreased ATP production. Pharmacologic targeting of Aβ-challenged neurons with a set of small molecules of known antioxidant and cytoprotective activity prevented the metabolic/bioenergetic changes induced by the peptide, fully restoring mitochondrial function while inducing an antioxidant response that counterbalanced the ROS production. Search for a mechanistic link among the protective small molecules tested identified the transcription factor Nrf2compromised by age and downregulated in AD and transgenic models-as their main target and the PI3K/GSK-3 axis as the central pathway through which the compounds elicit their Aβ protective action. Conclusions:Our study provides insights into the complex molecular mechanisms triggered by oligAβ which profoundly affect mitochondrial performance and argues for the inclusion of small molecules targeting the PI3K/ GSK-3 axis and Nrf2-mediated pathways as part of the current or future combinatorial therapies.

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Section: Discussionmentioning

confidence: 99%

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

2020

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“…Taken together, all these findings suggest that propolis displays neuroprotective through multiple pathways which might be attributed by the presence of bioactive compounds in propolis as well as their combination of multitarget compound acting on the different pathways. Several studies have reported on the neuroprotective effect of compounds present in the propolis in various study models of neurodegenerative diseases; for example, kaempferol [80,83], chrysin [84], pinocembrin [85][86][87][88][89][90][91][92][93][94][95][96], and caffeic acid phenethyl ester [97][98][99][100][101][102][103][104][105][106][107][108]. ese studies reported and suggested that these bioactive compounds may protect against neurodegenerative characteristics of neurodegenerative diseases Evidence-Based Complementary and Alternative Medicine and the multiple mechanisms of the neuroprotective effect of compounds tested could be potentially involved.…”

Section: Neuroprotective Activities Of Natural Products and Their Biomentioning

confidence: 99%

Natural Products and Their Bioactive Compounds: Neuroprotective Potentials against Neurodegenerative Diseases

Sairazi

Sirajudeen

2020

Evidence-Based Complementary and Alternative Medicine

142

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In recent years, natural products, which originate from plants, animals, and fungi, together with their bioactive compounds have been intensively explored and studied for their therapeutic potentials for various diseases such as cardiovascular, diabetes, hypertension, reproductive, cancer, and neurodegenerative diseases. Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are characterized by the progressive dysfunction and loss of neuronal structure and function that resulted in the neuronal cell death. Since the multifactorial pathological mechanisms are associated with neurodegeneration, targeting multiple mechanisms of actions and neuroprotection approach, which involves preventing cell death and restoring the function to damaged neurons, could be promising strategies for the prevention and therapeutic of neurodegenerative diseases. Natural products have emerged as potential neuroprotective agents for the treatment of neurodegenerative diseases. This review focused on the therapeutic potential of natural products and their bioactive compounds to exert a neuroprotective effect on the pathologies of neurodegenerative diseases.

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“…Finally, in order to link the antioxidant effect of CXB with HO-1 over-expression, experiments with the HO-inhibitor ZnPP-IX have been performed according to current literature ( Catino et al, 2015 ; Wang et al, 2016 ; Hui et al, 2018 ). As shown in Figures 7C,D , 2.5 μM ZnPP-IX fully counteracted 10 μM CXB-related ROS generation in SH-SY5Y cells treated with 25 nM sAβ, whereas the inhibitor only partially reverted ROS generation in 6.25 nM fAβ-exposed SH-SY5Y cells ( Figure 7C , One-way ANOVA followed by Tukey’s test, ° P < 0.001 vs. sAβ+CXB; Figure 7D , One-way ANOVA followed by Tukey’s test, ° P < 0.05 vs. fAβ+CXB).…”

Section: Resultsmentioning

confidence: 99%

Celecoxib Exerts Neuroprotective Effects in β-Amyloid-Treated SH-SY5Y Cells Through the Regulation of Heme Oxygenase-1: Novel Insights for an Old Drug

Mhillaj

Papi

Paciello

et al. 2020

Front. Cell Dev. Biol.

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The formation and aggregation of amyloid-β-peptide (Aβ) into soluble and insoluble species represent the pathological hallmarks of Alzheimer’s disease (AD). Over the last few years, however, soluble Aβ (sAβ) prevailed over fibrillar Aβ (fAβ) as determinant of neurotoxicity. One of the main therapeutic strategies for challenging neurodegeneration is to fight against neuroinflammation and prevent free radical-induced damage: in this light, the heme oxygenase/biliverdin reductase (HO/BVR) system is considered a promising drug target. The aim of this work was to investigate whether or not celecoxib (CXB), a selective inhibitor of the pro-inflammatory cyclooxygenase-2, modulates the HO/BVR system and prevents lipid peroxidation in SH-SY5Y neuroblastoma cells. Both sAβ (6.25–50 nM) and fAβ (1.25–50 nM) dose-dependently over-expressed inducible HO (HO-1) after 24 h of incubation, reaching statistical significance at 25 and 6.25 nM, respectively. Interestingly, CXB (1–10 μM, for 1 h) further enhanced Aβ-induced HO-1 expression through the nuclear translocation of the transcriptional factor Nrf2. Furthermore, 10 μM CXB counteracted the Aβ-induced ROS production with a mechanism fully dependent on HO-1 up-regulation; nevertheless, 10 μM CXB significantly counteracted only 25 nM sAβ-induced lipid peroxidation damage in SH-SY5Y neurons by modulating HO-1. Both carbon monoxide (CORM-2, 50 nM) and bilirubin (50 nM) significantly prevented ROS production in Aβ-treated neurons and favored both the slowdown of the growth rate of Aβ oligomers and the decrease in oligomer/fibril final size. In conclusion, these results suggest a novel mechanism through which CXB is neuroprotective in subjects with early AD or mild cognitive impairment.

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Inhibition of beta-amyloid-induced neurotoxicity by pinocembrin through Nrf2/HO-1 pathway in SH-SY5Y cells

Cited by 81 publications

References 41 publications

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

Natural Products and Their Bioactive Compounds: Neuroprotective Potentials against Neurodegenerative Diseases

Celecoxib Exerts Neuroprotective Effects in β-Amyloid-Treated SH-SY5Y Cells Through the Regulation of Heme Oxygenase-1: Novel Insights for an Old Drug

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