Home > Publications Database > Exploring the neuroprotective potential of Nrf2-pathway activators against annonacin toxicity. > print

001     271881
005     20250127091558.0
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037 _ _ |a DZNE-2024-01093
041 _ _ |a English
082 _ _ |a 600
100 1 _ |a Costa, Marcia F D
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245 _ _ |a Exploring the neuroprotective potential of Nrf2-pathway activators against annonacin toxicity.
260 _ _ |a [London]
|c 2024
|b Macmillan Publishers Limited, part of Springer Nature
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520 _ _ |a Modulation of the Nrf2 pathway, a master regulator of the antioxidant response and cellular metabolism, has been suggested as a promising therapeutic strategy in tauopathies, a heterogeneous group of neurodegenerative disorders characterized by intracellular proteinaceous inclusions of abnormally phosphorylated tau. Here, we explored the neuroprotective potential of different Nrf2-pathway activators in human immortalized dopaminergic neurons against annonacin-induced toxicity, a mitochondrial inhibitor associated with a PSP-like syndrome and capable of mimicking tauopathy-like features. Interestingly, we observed heterogenous and compound-dependent neuroprotective effects among the different Nrf2-pathway activators. With the exception of Fyn inhibitors, all the selected Nrf2-pathway activators improved cell viability and the oxidative status, and reduced the annonacin-induced tau hyperphosphorylation and neurite degeneration, particularly the p62-activators. However, improvement of the impaired mitochondrial function was only observed by the Bach-1 inhibitor. Surprisingly, we found evidence that ezetimibe, an approved drug for hypercholesterolemia, prevents the transcriptional upregulation of 4R-tau triggered by annonacin insult. Overall, our results suggest that the neuroprotective effects of the Nrf2-pathway activators against annonacin toxicity may rely on the specific mechanism of action, intrinsic to each compound, and possibly on the concomitant modulation of additional signaling pathways. Further research will be needed to fully understand how synergistic modulation of metabolic adaptation and cell survival can be exploit to develop new therapeutical strategies for tauopathies and eventually other neurodegenerative diseases.
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650 _ 7 |a NF-E2-Related Factor 2
|2 NLM Chemicals
650 _ 7 |a Neuroprotective Agents
|2 NLM Chemicals
650 _ 7 |a annonacin
|0 40372ET6TM
|2 NLM Chemicals
650 _ 7 |a NFE2L2 protein, human
|2 NLM Chemicals
650 _ 7 |a tau Proteins
|2 NLM Chemicals
650 _ 7 |a Benzofurans
|2 NLM Chemicals
650 _ 7 |a Furans
|2 NLM Chemicals
650 _ 7 |a Lactones
|2 NLM Chemicals
650 _ 2 |a NF-E2-Related Factor 2: metabolism
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Neuroprotective Agents: pharmacology
|2 MeSH
650 _ 2 |a Signal Transduction: drug effects
|2 MeSH
650 _ 2 |a Cell Survival: drug effects
|2 MeSH
650 _ 2 |a Oxidative Stress: drug effects
|2 MeSH
650 _ 2 |a Mitochondria: metabolism
|2 MeSH
650 _ 2 |a Mitochondria: drug effects
|2 MeSH
650 _ 2 |a Dopaminergic Neurons: drug effects
|2 MeSH
650 _ 2 |a Dopaminergic Neurons: metabolism
|2 MeSH
650 _ 2 |a tau Proteins: metabolism
|2 MeSH
650 _ 2 |a Phosphorylation: drug effects
|2 MeSH
650 _ 2 |a Cell Line
|2 MeSH
650 _ 2 |a Benzofurans: pharmacology
|2 MeSH
650 _ 2 |a Furans
|2 MeSH
650 _ 2 |a Lactones
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700 1 _ |a Rösler, Thomas W
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700 1 _ |a Höglinger, Günter U
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773 _ _ |a 10.1038/s41598-024-70837-1
|g Vol. 14, no. 1, p. 20123
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|t Scientific reports
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|x 2045-2322
856 4 _ |u https://pub.dzne.de/record/271881/files/DZNE-2024-01093%20SUP.docx
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