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@ARTICLE{Costa:271881,
      author       = {Costa, Marcia F D and Rösler, Thomas W and Höglinger,
                      Günter U},
      title        = {{E}xploring the neuroprotective potential of {N}rf2-pathway
                      activators against annonacin toxicity.},
      journal      = {Scientific reports},
      volume       = {14},
      number       = {1},
      issn         = {2045-2322},
      address      = {[London]},
      publisher    = {Macmillan Publishers Limited, part of Springer Nature},
      reportid     = {DZNE-2024-01093},
      pages        = {20123},
      year         = {2024},
      abstract     = {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.},
      keywords     = {NF-E2-Related Factor 2: metabolism / Humans /
                      Neuroprotective Agents: pharmacology / Signal Transduction:
                      drug effects / Cell Survival: drug effects / Oxidative
                      Stress: drug effects / Mitochondria: metabolism /
                      Mitochondria: drug effects / Dopaminergic Neurons: drug
                      effects / Dopaminergic Neurons: metabolism / tau Proteins:
                      metabolism / Phosphorylation: drug effects / Cell Line /
                      Benzofurans: pharmacology / Furans / Lactones /
                      NF-E2-Related Factor 2 (NLM Chemicals) / Neuroprotective
                      Agents (NLM Chemicals) / annonacin (NLM Chemicals) / NFE2L2
                      protein, human (NLM Chemicals) / tau Proteins (NLM
                      Chemicals) / Benzofurans (NLM Chemicals) / Furans (NLM
                      Chemicals) / Lactones (NLM Chemicals)},
      cin          = {Clinical Research (Munich) / AG Höglinger ; AG Höglinger},
      ddc          = {600},
      cid          = {I:(DE-2719)1111015 / I:(DE-2719)1110002},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC11362529},
      pubmed       = {pmid:39209951},
      doi          = {10.1038/s41598-024-70837-1},
      url          = {https://pub.dzne.de/record/271881},
}