Skip to main content

Advertisement

SpringerLink
Log in

Edaravone Attenuates Aβ 1-42-Induced Inflammatory Damage and Ferroptosis in HT22 Cells

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Ferroptosis and neuroinflammation play a crucial role in the pathogenesis of Alzheimer’s disease (AD), and Edaravone (EDA) has been demonstrated to have anti-inflammatory, antioxidant and neuroprotective effects in neurodegenerative diseases. However, the relationship between EDA and ferroptosis in AD is unidentified. This research aimed to elucidate the mechanism of EDA in AD with Aβ 1-42-induced HT22 cells as in vitro cell model. The results showed that EDA could significantly reduce Aβ1-42-induced apoptosis of HT22 cells and formation of pro-inflammatory factors TNF-α, IL-1β and IL-6, prevent the activation of TLR4/NF-κB /NLRP3 signaling pathway, and inhibit ferroptosis and lipid peroxidation. Taken together, EDA contributes to inhibiting neuroinflammatory injury and ferroptosis in Aβ 1-42-induced HT22 cells, and thus may be a potential candidate for the treatment of AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

The datasets used and analysed in the current study are available from the corresponding author on reasonable request.

References

  1. Anand R, Gill K, Mahdi A (2014) Therapeutics of Alzheimer’s disease: past, present and future. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2013.07.004

    Article  Google Scholar 

  2. Scheltens P, Blennow K, Breteler M, de Strooper B, Frisoni G, Salloway S, Van der Flier W (2016) Alzheimer’s disease. Lancet (London, England) 388:505–517. https://doi.org/10.1016/s0140-6736(15)01124-1

    Article  CAS  Google Scholar 

  3. Park J, Kim S, Kim S, Jo M, Choi M, Kim M (2019) A novel kit for early diagnosis of Alzheimer’s disease using a fluorescent nanoparticle imaging. Sci Rep 9:13184. https://doi.org/10.1038/s41598-019-49711-y

    Article  CAS  Google Scholar 

  4. Li LJ, Chen ZW, Zhong XF, Huang JF, Yu Q, Carlsson C, Okonkwo O (2019) Sweetening the process of biomarker discovery in Alzheimer’s disease: development of improved chemical strategies for probing glycosylation patterns in AD. In: Abstracts of Papers of The American Chemical Society

  5. Cai Y, Chai Y, Fu Y, Wang Y, Zhang Y, Zhang X, Zhu L, Miao M, Yan T (2021) Salidroside Ameliorates Alzheimer’s disease by targeting NLRP3 inflammasome-mediated pyroptosis. Front Aging Neurosci 13:809433. https://doi.org/10.3389/fnagi.2021.809433

    Article  CAS  Google Scholar 

  6. World Alzheimer Report (2021) Alzheimer Diseases International. https://www.alzint.org/resource/world-alzheimer-report-2021/

  7. Emre C, Do K, Jun B, Hjorth E, Alcalde S, Kautzmann M, Gordon W, Nilsson P, Bazan N, Schultzberg M (2021) Age-related changes in brain phospholipids and bioactive lipids in the APP knock-in mouse model of Alzheimer’s disease. Acta Neuropathol Commun 9:116. https://doi.org/10.1186/s40478-021-01216-4

    Article  CAS  Google Scholar 

  8. Zhuang W, Yue L, Dang X, Chen F, Gong Y, Lin X, Luo Y (2019) Rhodiola Rosenroot (): potential applications in aging-related diseases. Aging Dis 10:134–146. https://doi.org/10.14336/ad.2018.0511

    Article  Google Scholar 

  9. Mangalmurti A, Lukens J (2022) How neurons die in Alzheimer’s disease: implications for neuroinflammation. Curr Opin Neurobiol 75:102575. https://doi.org/10.1016/j.conb.2022.102575

    Article  CAS  Google Scholar 

  10. Sun Y, Xia X, Basnet D, Zheng J, Huang J, Liu J (2022) Mechanisms of ferroptosis and emerging links to the pathology of neurodegenerative diseases. Front Aging Neurosci 14:904152. https://doi.org/10.3389/fnagi.2022.904152

    Article  CAS  Google Scholar 

  11. Ayton S, Portbury S, Kalinowski P, Agarwal P, Diouf I, Schneider J, Morris M, Bush A (2021) Regional brain iron associated with deterioration in Alzheimer’s disease: a large cohort study and theoretical significance. Alzheimer’s Dement J Alzheimer’s Assoc 17:1244–1256. https://doi.org/10.1002/alz.12282

    Article  Google Scholar 

  12. Wei Y, Lv H, Shaikh A, Han W, Hou H, Zhang Z, Wang S, Shang P (2020) Directly targeting glutathione peroxidase 4 may be more effective than disrupting glutathione on ferroptosis-based cancer therapy. Biochim Biophys Acta Gen Subj 1864:129539. https://doi.org/10.1016/j.bbagen.2020.129539

    Article  CAS  Google Scholar 

  13. Yu H, Guo P, Xie X, Wang Y, Chen G (2017) Ferroptosis, a new form of cell death, and its relationships with tumourous diseases. J Cell Mol Med 21:648–657. https://doi.org/10.1111/jcmm.13008

    Article  CAS  Google Scholar 

  14. Hassannia B, Vandenabeele P, Vanden Berghe T (2019) Targeting ferroptosis to iron out cancer. Cancer Cell 35:830–849. https://doi.org/10.1016/j.ccell.2019.04.002

    Article  CAS  Google Scholar 

  15. Wen Y, Chen H, Zhang L, Wu M, Zhang F, Yang D, Shen J, Chen J (2021) Glycyrrhetinic acid induces oxidative/nitrative stress and drives ferroptosis through activating NADPH oxidases and iNOS, and depriving glutathione in triple-negative breast cancer cells. Free Radic Biol Med 173:41–51. https://doi.org/10.1016/j.freeradbiomed.2021.07.019

    Article  CAS  Google Scholar 

  16. Friedmann Angeli J, Schneider M, Proneth B, Tyurina Y, Tyurin V, Hammond V, Herbach N, Aichler M, Walch A, Eggenhofer E, Basavarajappa D, Rådmark O, Kobayashi S, Seibt T, Beck H, Neff F, Esposito I, Wanke R, Förster H, Yefremova O, Heinrichmeyer M, Bornkamm G, Geissler E, Thomas S, Stockwell B, O’Donnell V, Kagan V, Schick J, Conrad M (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16:1180–1191. https://doi.org/10.1038/ncb3064

    Article  CAS  Google Scholar 

  17. Shan Y, Li J, Zhu A, Kong W, Ying R, Zhu W (2022) Ginsenoside Rg3 ameliorates acute pancreatitis by activating the NRF2/HO–1–mediated ferroptosis pathway. Int J Mol Med. https://doi.org/10.3892/ijmm.2022.5144

    Article  Google Scholar 

  18. Xiang Z, Zhou X, Mranda G, Xue Y, Wang Y, Wei T, Liu J, Ding Y (2022) Identification of the ferroptosis-related ceRNA network related to prognosis and tumor immunity for gastric cancer. Aging. https://doi.org/10.18632/aging.204176

    Article  Google Scholar 

  19. Yang S, Xie Z, Pei T, Zeng Y, Xiong Q, Wei H, Wang Y, Cheng W (2022) Salidroside attenuates neuronal ferroptosis by activating the Nrf2/HO1 signaling pathway in Aβ-induced Alzheimer’s disease mice and glutamate-injured HT22 cells. Chin Med 17:82. https://doi.org/10.1186/s13020-022-00634-3

    Article  CAS  Google Scholar 

  20. Feng T, Yamashita T, Sasaki R, Tadokoro K, Matsumoto N, Hishikawa N, Abe K (2021) Protective effects of edaravone on white matter pathology in a novel mouse model of Alzheimer’s disease with chronic cerebral hypoperfusion. J Cereb Blood Flow Metab 41:1437–1448. https://doi.org/10.1177/0271678x20968927

    Article  CAS  Google Scholar 

  21. Writing G, Edaravone ALSSG (2017) Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 16:505–512. https://doi.org/10.1016/S1474-4422(17)30115-1

    Article  Google Scholar 

  22. Edaravone Acute Infarction Study G (2003) Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis 15:222–229. https://doi.org/10.1159/000069318

    Article  CAS  Google Scholar 

  23. Wang H, Zhang T, Huang J, Xiang J, Chen J, Fu J, Zhao Y (2017) Edaravone attenuates the proinflammatory response in amyloid-β-treated microglia by inhibiting NLRP3 inflammasome-mediated IL-1β secretion. Cell Physiol Biochem 43:1113–1125. https://doi.org/10.1159/000481753

    Article  CAS  Google Scholar 

  24. Zhang G, Zhang L, Guo Y, Ma Z, Wang H, Li T, Liu J, Du Y, Yao L, Li T, Du J (2017) Protective effect of edaravone against Aβ25-35-induced mitochondrial oxidative damage in SH-SY5Y cells. Cell Mol Biol (Noisy-le-Grand France) 63:36–42. https://doi.org/10.14715/cmb/2017.63.5.8

    Article  Google Scholar 

  25. Zhao X, Huang X, Yang C, Jiang Y, Zhou W, Zheng W (2022) Artemisinin attenuates amyloid-induced brain inflammation and memory impairments by modulating TLR4/NF-kappaB signaling. Int J Mol Sci. https://doi.org/10.3390/ijms23116354

    Article  Google Scholar 

  26. Zhao Z, Luan P, Huang S, Xiao S, Zhao J, Zhang B, Gu B, Pi R, Liu J (2013) Edaravone protects HT22 neurons from H2O2-induced apoptosis by inhibiting the MAPK signaling pathway. CNS Neurosci Ther 19:163–169. https://doi.org/10.1111/cns.12044

    Article  CAS  Google Scholar 

  27. Liu J, Yan X, Qi L, Li L, Hu G, Li P, Zhao G (2015) Ginsenoside Rd attenuates Aβ25-35-induced oxidative stress and apoptosis in primary cultured hippocampal neurons. Chemico-Biol Interact 239:12–18. https://doi.org/10.1016/j.cbi.2015.06.030

    Article  CAS  Google Scholar 

  28. Shen Y, Wang Y, Yu G, Liu C, Zhang Z, Zhang L (2013) Effects of edaravone on amyloid-β precursor protein processing in SY5Y-APP695 cells. Neurotox Res 24:139–147. https://doi.org/10.1007/s12640-012-9370-3

    Article  CAS  Google Scholar 

  29. Zhang Z, Han K, Wang C, Sun C, Jia N (2020) Dioscin protects against Aβ1–42 oligomers-induced neurotoxicity via the function of SIRT3 and autophagy. Chem Pharm Bull 68:717–725. https://doi.org/10.1248/cpb.c20-00046

    Article  CAS  Google Scholar 

  30. Sharma P, Srivastava P, Seth A, Tripathi P, Banerjee A, Shrivastava S (2019) Comprehensive review of mechanisms of pathogenesis involved in Alzheimer’s disease and potential therapeutic strategies. Prog Neurobiol 174:53–89. https://doi.org/10.1016/j.pneurobio.2018.12.006

    Article  CAS  Google Scholar 

  31. Wang F, Wang J, Shen Y, Li H, Rausch W, Huang X (2022) Iron dyshomeostasis and ferroptosis: a new Alzheimer’s disease hypothesis? Front Aging Neurosci 14:830569. https://doi.org/10.3389/fnagi.2022.830569

    Article  CAS  Google Scholar 

  32. Muresan V, Ladescu Muresan Z (2015) Amyloid-β precursor protein: multiple fragments, numerous transport routes and mechanisms. Exp Cell Res 334:45–53. https://doi.org/10.1016/j.yexcr.2014.12.014

    Article  CAS  Google Scholar 

  33. Canter R, Penney J, Tsai L (2016) The road to restoring neural circuits for the treatment of Alzheimer’s disease. Nature 539:187–196. https://doi.org/10.1038/nature20412

    Article  Google Scholar 

  34. Yoon S, Kim YK (2015) The role of immunity and neuroinflammation in genetic predisposition and pathogenesis of Alzheimer’s disease. Aims Genet 2:230–249

    Article  Google Scholar 

  35. Choi A, Ryter S, Levine B (2013) Autophagy in human health and disease. N Engl J Med 368:651–662. https://doi.org/10.1056/NEJMra1205406

    Article  CAS  Google Scholar 

  36. Kuperstein I, Broersen K, Benilova I, Rozenski J, Jonckheere W, Debulpaep M, Vandersteen A, Segers-Nolten I, Van Der Werf K, Subramaniam V, Braeken D, Callewaert G, Bartic C, D’Hooge R, Martins I, Rousseau F, Schymkowitz J, De Strooper B (2010) Neurotoxicity of Alzheimer’s disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio. EMBO J 29:3408–3420. https://doi.org/10.1038/emboj.2010.211

    Article  CAS  Google Scholar 

  37. Iijima K, Liu H, Chiang A, Hearn S, Konsolaki M, Zhong Y (2004) Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer’s disease. Proc Natl Acad Sci USA 101:6623–6628. https://doi.org/10.1073/pnas.0400895101

    Article  CAS  Google Scholar 

  38. Younkin S (1995) Evidence that A beta 42 is the real culprit in Alzheimer’s disease. Ann Neurol 37:287–288. https://doi.org/10.1002/ana.410370303

    Article  CAS  Google Scholar 

  39. Zheng M, Liu J, Ruan Z, Tian S, Ma Y, Zhu J, Li G (2013) Intrahippocampal injection of Aβ1–42 inhibits neurogenesis and down-regulates IFN-γ and NF-κB expression in hippocampus of adult mouse brain. Amyloid 20:13–20. https://doi.org/10.3109/13506129.2012.755122

    Article  CAS  Google Scholar 

  40. Wilms H, Sievers J, Rickert U, Rostami-Yazdi M, Mrowietz U, Lucius R (2010) Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1beta, TNF-alpha and IL-6 in an in-vitro model of brain inflammation. J Neuroinflamm 7:30. https://doi.org/10.1186/1742-2094-7-30

    Article  CAS  Google Scholar 

  41. Zhou H, Niu D, Xue B, Li F, Liu X, He Q, Wang X, Wang X (2003) Triptolide inhibits TNF-alpha, IL-1 beta and NO production in primary microglial cultures. NeuroReport 14:1091–1095. https://doi.org/10.1097/01.wnr.0000073682.00308.47

    Article  CAS  Google Scholar 

  42. Huang X, Li J, Tao Y, Wang X, Zhang R, Zhang J, Su Z, Huang Q, Deng Y (2018) viaGeniposide attenuates Aβ-induced neurotoxicity the TLR4/NF-κB pathway in HT22 cells. RSC Adv 8:18926–18937. https://doi.org/10.1039/c8ra01038b

    Article  CAS  Google Scholar 

  43. Liu M, Xie J, Sun Y (2020) TLR4/MyD88/NF-κB-mediated inflammation contributes to cardiac dysfunction in rats of PTSD. Cell Mol Neurobiol 40:1029–1035. https://doi.org/10.1007/s10571-020-00791-9

    Article  CAS  Google Scholar 

  44. Guo H, Callaway J, Ting J (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21:677–687. https://doi.org/10.1038/nm.3893

    Article  CAS  Google Scholar 

  45. Cui W, Sun C, Ma Y, Wang S, Wang X, Zhang Y (2020) Inhibition of TLR4 induces M2 microglial polarization and provides neuroprotection via the NLRP3 inflammasome in Alzheimer’s Disease. Front NeuroSci 14:444. https://doi.org/10.3389/fnins.2020.00444

    Article  Google Scholar 

  46. Zhang B, Lian W, Zhao J, Wang Z, Liu A, Du G (2021) DL0410 alleviates memory impairment in D-galactose-induced aging rats by suppressing neuroinflammation via the TLR4/MyD88/NF-kappaB pathway. Oxid Med Cell Longev 2021:6521146. https://doi.org/10.1155/2021/6521146

    Article  CAS  Google Scholar 

  47. Calvo-Rodriguez M, Garcia-Rodriguez C, Villalobos C, Nunez L (2020) Role of toll like receptor 4 in Alzheimer’s disease. Front Immunol 11:1588. https://doi.org/10.3389/fimmu.2020.01588

    Article  CAS  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Department II of Neurology, Shaanxi Provincial People’s Hospital, Xi’an, 710068, Shaanxi, China

    Shenglong Guo, Qi Lei, Hena Guo, Qian Yang, Yanli Xue & Ruili Chen

Authors
  1. Shenglong Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qi Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hena Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qian Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yanli Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ruili Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SG and RC wrote the paper and conceived and designed the experiments; QL and HG analyzed the data; QY and YX collected and provided the sample for this study. All authors reviewed the manuscript.

Corresponding author

Correspondence to Ruili Chen.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, S., Lei, Q., Guo, H. et al. Edaravone Attenuates Aβ 1-42-Induced Inflammatory Damage and Ferroptosis in HT22 Cells. Neurochem Res 48, 570–578 (2023). https://doi.org/10.1007/s11064-022-03782-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-022-03782-y

Keywords

Search

Navigation