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New Probucol Analogues Inhibit Ferroptosis, Improve Mitochondrial Parameters, and Induce Glutathione Peroxidase in HT22 Cells

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Abstract

Probucol, a hypocholesterolemic compound, is neuroprotective in several models of neurodegenerative diseases but has serious adverse effects in vivo. We now describe the design and synthesis of two new probucol analogues that protect against glutamate-induced oxidative cell death, also known as ferroptosis, in cultured mouse hippocampal (HT22) cells and in primary cortical neurons, while probucol did not show any protective effect. Treatment with both compounds did not affect glutathione depletion but still significantly decreased glutamate-induced production of oxidants, mitochondrial superoxide generation, and mitochondrial hyperpolarization in HT22 cells. Both compounds increase glutathione peroxidase (GPx) 1 levels and GPx activity, also exhibiting protection against RSL3, a GPx4 inactivator. These two compounds are therefore potent activators of GPx activity making further studies of their neuroprotective activity in vivo worthwhile.

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Abbreviations

3-NA:

3-Nitropropionic acid

6-OHDA:

6-Hydroxydopamine

BSO:

Buthionine sulfoximine

CAT:

Catalase

CTB:

CellTiter-Blue

GCL:

Glycine cysteine ligase

DCFH-DA:

2′,7′-Dichlorofluorescein diacetate

DMEM:

Dulbecco’s Modified Eagle Medium

DMSO:

Dimethyl sulfoxide

ETS:

Electron transfer system

FBS:

Fetal bovine serum

FCCP:

Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone

Glu:

Glutamate

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

GSH:

Glutathione

HBSS:

Hank’s balanced salt solution

MeHg:

Methylmercury

MMP:

Mitochondrial membrane potential

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MSA:

β-Mercaptosuccinic acid

MTT:

3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide

NPSH:

Non-protein thiol

O2•− :

Anion superoxide

PB:

Probucol

PI:

Propidium iodide

SOD:

Superoxide dismutase

STZ:

Streptozotocin

tBuOOH:

tert-butyl hydroperoxide

References

  1. Yamashita S, Matsuzawa Y (2009) Where are we with probucol: a new life for an old drug? Atherosclerosis 207(1):16–23. https://doi.org/10.1016/j.atherosclerosis.2009.04.002

    Article  CAS  PubMed  Google Scholar 

  2. Yamashita S, Masuda D, Matsuzawa Y (2015) Did we abandon probucol too soon? Curr Opin Lipidol 26(4):304–316. https://doi.org/10.1097/mol.0000000000000199

    Article  CAS  PubMed  Google Scholar 

  3. Colle D, Hartwig JM, Antunes Soares FA, Farina M (2012) Probucol modulates oxidative stress and excitotoxicity in Huntington’s disease models in vitro. Brain Res Bull 87(4–5):397–405. https://doi.org/10.1016/j.brainresbull.2012.01.003

    Article  CAS  PubMed  Google Scholar 

  4. Colle D, Santos DB, Moreira ELG, Hartwig JM, dos Santos AA, Zimmermann LT, Hort MA, Farina M (2013) Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats. PLoS One 8(6):e67658. https://doi.org/10.1371/journal.pone.0067658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Santos DB, Peres KC, Ribeiro RP, Colle D, AAd S, ELG M, DOG S, Figueiredo CP et al (2012) Probucol, a lipid-lowering drug, prevents cognitive and hippocampal synaptic impairments induced by amyloid β peptide in mice. Exp Neurol 233(2):767–775. https://doi.org/10.1016/j.expneurol.2011.11.036

    Article  CAS  PubMed  Google Scholar 

  6. Santos DB, Colle D, Moreira ELG, Peres KC, Ribeiro RP, dos Santos AA, de Oliveira J, Hort MA et al (2015) Probucol mitigates streptozotocin-induced cognitive and biochemical changes in mice. Neuroscience 284:590–600. https://doi.org/10.1016/j.neuroscience.2014.10.019

    Article  CAS  PubMed  Google Scholar 

  7. Ribeiro RP, Moreira ELG, Santos DB, Colle D, dos Santos AA, Peres KC, Figueiredo CP, Farina M (2013) Probucol affords neuroprotection in a 6-OHDA mouse model of Parkinson’s disease. Neurochem Res 38(3):660–668. https://doi.org/10.1007/s11064-012-0965-0

    Article  CAS  PubMed  Google Scholar 

  8. Farina M, Campos F, Vendrell I, Berenguer J, Barzi M, Pons S, Suñol C (2009) Probucol increases glutathione peroxidase-1 activity and displays long-lasting protection against methylmercury toxicity in cerebellar granule cells. Toxicol Sci 112(2):416–426. https://doi.org/10.1093/toxsci/kfp219

    Article  CAS  PubMed  Google Scholar 

  9. Stocker R (2009) Molecular mechanisms underlying the antiatherosclerotic and antidiabetic effects of probucol, succinobucol, and other probucol analogues. Curr Opin Lipidol 20(3):227–235. https://doi.org/10.1097/MOL.0b013e32832aee68

    Article  CAS  PubMed  Google Scholar 

  10. Tardif J-C, Grégoire J, Schwartz L, Title L, Laramée L, Reeves F, Lespérance J, Bourassa MG et al (2003) Effects of AGI-1067 and probucol after percutaneous coronary interventions. Circulation 107(4):552–558. https://doi.org/10.1161/01.CIR.0000047525.58618.3C

    Article  CAS  PubMed  Google Scholar 

  11. Colle D, Santos DB, Hartwig JM, Godoi M, Engel DF, de Bem AF, Braga AL, Farina M (2016) Succinobucol, a lipid-lowering drug, protects against 3-nitropropionic acid-induced mitochondrial dysfunction and oxidative stress in SH-SY5Y cells via upregulation of glutathione levels and glutamate cysteine ligase activity. Mol Neurobiol 53(2):1280–1295. https://doi.org/10.1007/s12035-014-9086-x

    Article  CAS  PubMed  Google Scholar 

  12. Santos DB, Colle D, Moreira ELG, Hort MA, Godoi M, Le Douaron G, Braga AL, Assreuy J et al (2017) Succinobucol, a non-statin hypocholesterolemic drug, prevents premotor symptoms and nigrostriatal neurodegeneration in an experimental model of Parkinson’s disease. Mol Neurobiol 54(2):1513–1530. https://doi.org/10.1007/s12035-016-9747-z

    Article  CAS  PubMed  Google Scholar 

  13. Davis JB, Maher P (1994) Protein kinase C activation inhibits glutamate-induced cytotoxicity in a neuronal cell line. Brain Res 652(1):169–173. https://doi.org/10.1016/0006-8993(94)90334-4

    Article  CAS  PubMed  Google Scholar 

  14. Albrecht P, Henke N, Tien M-LT, Issberner A, Bouchachia I, Maher P, Lewerenz J, Methner A (2013) Extracellular cyclic GMP and its derivatives GMP and guanosine protect from oxidative glutamate toxicity. Neurochem Int 62(5):610–619. https://doi.org/10.1016/j.neuint.2013.01.019

    Article  CAS  PubMed  Google Scholar 

  15. Lewerenz J, Sato H, Albrecht P, Henke N, Noack R, Methner A, Maher P (2012) Mutation of ATF4 mediates resistance of neuronal cell lines against oxidative stress by inducing xCT expression. Cell Death Differ 19(5):847–858 http://www.nature.com/cdd/journal/v19/n5/suppinfo/cdd2011165s1.html

    Article  CAS  PubMed  Google Scholar 

  16. Maher P, van Leyen K, Dey PN, Honrath B, Dolga A, Methner A (2018) The role of Ca2+ in cell death caused by oxidative glutamate toxicity and ferroptosis. Cell Calcium 70:47–55. https://doi.org/10.1016/j.ceca.2017.05.007

    Article  CAS  PubMed  Google Scholar 

  17. Henke N, Albrecht P, Bouchachia I, Ryazantseva M, Knoll K, Lewerenz J, Kaznacheyeva E, Maher P et al (2013) The plasma membrane channel ORAI1 mediates detrimental calcium influx caused by endogenous oxidative stress. Cell Death Dis 4:e470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dixon Scott J, Lemberg Kathryn M, Lamprecht Michael R, Skouta R, Zaitsev Eleina M, Gleason Caroline E, Patel Darpan N, Bauer Andras J et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072. https://doi.org/10.1016/j.cell.2012.03.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Albrecht P, Lewerenz J, Dittmer S, Noack R, Maher P, Methner A (2010) Mechanisms of oxidative glutamate toxicity: the glutamate/cystine antiporter system xc¯ as a neuroprotective drug target. CNS Neurol Disord Drug Targets 9(3):373–382. https://doi.org/10.2174/187152710791292567

    Article  CAS  PubMed  Google Scholar 

  20. Li J, Cao F, H-l Y, Z-j H, Lin Z-t, Mao N, Sun B, Wang G (2020) Ferroptosis: past, present and future. Cell Death Dis 11(2):88. https://doi.org/10.1038/s41419-020-2298-2

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lewerenz J, Ates G, Methner A, Conrad M, Maher P (2018) Oxytosis/FErroptosis—(re-) emerging roles for oxidative stress-dependent non-apoptotic cell death in diseases of the central nervous system. Front Neurosci 12:214. https://doi.org/10.3389/fnins.2018.00214

    Article  PubMed  PubMed Central  Google Scholar 

  22. Friedmann Angeli JP, Miyamoto S, Schulze A (2019) Ferroptosis: the greasy side of cell death. Chem Res Toxicol 32(3):362–369. https://doi.org/10.1021/acs.chemrestox.8b00349

    Article  CAS  PubMed  Google Scholar 

  23. Mao X-Y, Zhou H-H, Li X, Liu Z-Q (2016) Huperzine a alleviates oxidative glutamate toxicity in hippocampal HT22 cells via activating BDNF/TrkB-dependent PI3K/Akt/mTOR signaling pathway. Cell Mol Neurobiol 36(6):915–925. https://doi.org/10.1007/s10571-015-0276-5

    Article  CAS  PubMed  Google Scholar 

  24. Kumari S, Mehta SL, Milledge GZ, Huang X, Li H, Li PA (2016) Ubisol-Q10 prevents glutamate-induced cell death by blocking mitochondrial fragmentation and permeability transition pore opening. Int J Biol Sci 12(6):688–700. https://doi.org/10.7150/ijbs.13589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jin ML, Park SY, Kim YH, Oh J-I, Lee SJ, Park G (2014) The neuroprotective effects of cordycepin inhibit glutamate-induced oxidative and ER stress-associated apoptosis in hippocampal HT22 cells. NeuroToxicology 41:102–111. https://doi.org/10.1016/j.neuro.2014.01.005

    Article  CAS  PubMed  Google Scholar 

  26. Quispe RL, Canto RFS, Jaramillo ML, Barbosa FAR, Braga AL, de Bem AF, Farina M (2018) Design, synthesis, and in vitro evaluation of a novel probucol derivative: protective activity in neuronal cells through GPx upregulation. Mol Neurobiol 55(10):7619–7634. https://doi.org/10.1007/s12035-018-0939-6

    Article  CAS  PubMed  Google Scholar 

  27. Steinbeck JA, Henke N, Opatz J, Gruszczynska-Biegala J, Schneider L, Theiss S, Hamacher N, Steinfarz B et al (2011) Store-operated calcium entry modulates neuronal network activity in a model of chronic epilepsy. Exp Neurol 232(2):185–194. https://doi.org/10.1016/j.expneurol.2011.08.022

    Article  CAS  PubMed  Google Scholar 

  28. Ellman GL (1959) Tissue sulfhydryl groups, Arch Biochem Biophys. 82(1):70–77. https://doi.org/10.1016/0003-9861(59)90090-6

  29. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193(1):265–275

    CAS  PubMed  Google Scholar 

  30. Chazotte B (2011) Labeling mitochondria with JC-1. Cold Spring Harb Protoc 2011(9):pdb.prot065490. https://doi.org/10.1101/pdb.prot065490

    Article  PubMed  Google Scholar 

  31. Oppermann S, Schrader FC, Elsässer K, Dolga AM, Kraus AL, Doti N, Wegscheid-Gerlach C, Schlitzer M et al (2014) Novel <em>N</em>-phenyl–substituted thiazolidinediones protect neural cells against glutamate- and tBid-induced toxicity. J Pharmacol Exp Ther 350(2):273–289. https://doi.org/10.1124/jpet.114.213777

    Article  CAS  PubMed  Google Scholar 

  32. Lopes MW, Lopes SC, Costa AP, Gonçalves FM, Rieger DK, Peres TV, Eyng H, Prediger RD et al (2015) Region-specific alterations of AMPA receptor phosphorylation and signaling pathways in the pilocarpine model of epilepsy. Neurochem Int 87:22–33. https://doi.org/10.1016/j.neuint.2015.05.003

    Article  CAS  PubMed  Google Scholar 

  33. Peterson GL (1977) A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem 83(2):346–356. https://doi.org/10.1016/0003-2697(77)90043-4

    Article  CAS  PubMed  Google Scholar 

  34. Bjerrum OJ, Heegaard NHH (1988) CRC handbook of immunoblotting of proteins. CRC Press, Cleveland

    Google Scholar 

  35. Wendel A (1981) [44] Glutathione peroxidase. In: Methods in enzymology, vol 77. Academic Press, pp 325-333. https://doi.org/10.1016/S0076-6879(81)77046-0

  36. Panee J, Stoytcheva ZR, Liu W, Berry MJ (2007) Selenoprotein H is a redox-sensing high mobility group family DNA-binding protein that up-regulates genes involved in glutathione synthesis and phase II detoxification. J Biol Chem 282(33):23759–23765. https://doi.org/10.1074/jbc.M702267200

    Article  CAS  PubMed  Google Scholar 

  37. Mao SJT, Yates MT, Jackson RL (1994) [51] Antioxidant activity and serum levels of probucol and probucal metabolites. In: Methods in enzymology, vol 234. Academic Press, pp 505-513. https://doi.org/10.1016/0076-6879(94)34122-2

  38. Pinacho Crisóstomo FR, Carrillo R, León LG, Martín T, Padrón JM, Martín VS (2006) Molecular simplification in bioactive molecules: formal synthesis of (+)-muconin. J Organomet Chem 71(6):2339–2345. https://doi.org/10.1021/jo0524674

    Article  CAS  Google Scholar 

  39. Patani GA, LaVoie EJ (1996) Bioisosterism: a rational approach in drug design. Chem Rev 96(8):3147–3176. https://doi.org/10.1021/cr950066q

    Article  CAS  PubMed  Google Scholar 

  40. Kwong FY, Buchwald SL (2002) A general, efficient, and inexpensive catalyst system for the coupling of aryl iodides and thiols. Org Lett 4(20):3517–3520. https://doi.org/10.1021/ol0266673

    Article  CAS  PubMed  Google Scholar 

  41. Murphy TH, Miyamoto M, Sastre A, Schnaar RL, Coyle JT (1989) Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. Neuron 2(6):1547–1558. https://doi.org/10.1016/0896-6273(89)90043-3

    Article  CAS  PubMed  Google Scholar 

  42. Cooper AJL, Ta F (1998) Role of astrocytes in maintaining cerebral glutathione homeostasis and in protecting the brain against xenobiotics and oxidative stress. The role of glutathione in the nervous system, Washington, pp 91–115

  43. Fukui M, Song JH, Choi JY, Choi HJ, Zhu BT (2009) Mechanism of glutamate-induced neurotoxicity in HT22 mouse hippocampal cells. Eur J Pharmacol 617(1–3):1–11. https://doi.org/10.1016/j.ejphar.2009.06.059

    Article  CAS  PubMed  Google Scholar 

  44. Herrera F, Martin V, Garcia-Santos G, Rodriguez-Blanco J, Antolin I, Rodriguez C (2007) Melatonin prevents glutamate-induced oxytosis in the HT22 mouse hippocampal cell line through an antioxidant effect specifically targeting mitochondria. J Neurochem 100(3):736–746. https://doi.org/10.1111/j.1471-4159.2006.04228.x

    Article  CAS  PubMed  Google Scholar 

  45. Pallast S, Arai K, Wang XY, Lo EH, van Leyen K (2009) 12/15-Lipoxygenase targets neuronal mitochondria under oxidative stress. J Neurochem 111(3):882–889. https://doi.org/10.1111/j.1471-4159.2009.06379.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fukui M, Zhu BT (2010) Mitochondrial superoxide dismutase SOD2, but not cytosolic SOD1, plays a critical role in protection against glutamate-induced oxidative stress and cell death in HT22 neuronal cells. Free Radic Biol Med 48(6):821–830. https://doi.org/10.1016/j.freeradbiomed.2009.12.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tobaben S, Grohm J, Seiler A, Conrad M, Plesnila N, Culmsee C (2011) Bid-mediated mitochondrial damage is a key mechanism in glutamate-induced oxidative stress and AIF-dependent cell death in immortalized HT-22 hippocampal neurons. Cell Death Differ 18(2):282–292. https://doi.org/10.1038/cdd.2010.92

    Article  CAS  PubMed  Google Scholar 

  48. Pfeiffer A, Jaeckel M, Lewerenz J, Noack R, Pouya A, Schacht T, Hoffmann C, Winter J et al (2014) Mitochondrial function and energy metabolism in neuronal HT22 cells resistant to oxidative stress. Br J Pharmacol 171(8):2147–2158. https://doi.org/10.1111/bph.12549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhang C, Yuan X-r, Li H-y, Zhao Z-j, Liao Y-w, Wang X-y, Su J, Sang S-s et al (2014) Downregualtion of dynamin-related protein 1 attenuates glutamate-induced excitotoxicity via regulating mitochondrial function in a calcium dependent manner in HT22 cells. Biochem Biophys Res Commun 443(1):138–143. https://doi.org/10.1016/j.bbrc.2013.11.072

    Article  CAS  PubMed  Google Scholar 

  50. Sun S, Hu F, Wu J, Zhang S (2017) Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons. Redox Biol 11:577–585. https://doi.org/10.1016/j.redox.2016.12.029

    Article  CAS  PubMed  Google Scholar 

  51. Zhang YM, Bhavnani BR (2006) Glutamate-induced apoptosis in neuronal cells is mediated via caspase-dependent and independent mechanisms involving calpain and caspase-3 proteases as well as apoptosis inducing factor (AIF) and this process is inhibited by equine estrogens. BMC Neurosci 7:49. https://doi.org/10.1186/1471-2202-7-49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liu Y, Schubert DR (2009) The specificity of neuroprotection by antioxidants. J Biomed Sci 16(1):98. https://doi.org/10.1186/1423-0127-16-98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kumari S, Mehta SL, Li PA (2012) Glutamate induces mitochondrial dynamic imbalance and autophagy activation: preventive effects of selenium. PLoS One 7(6):e39382. https://doi.org/10.1371/journal.pone.0039382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Grohm J, Plesnila N, Culmsee C (2010) Bid mediates fission, membrane permeabilization and peri-nuclear accumulation of mitochondria as a prerequisite for oxidative neuronal cell death. Brain Behav Immun 24(5):831–838. https://doi.org/10.1016/j.bbi.2009.11.015

    Article  CAS  PubMed  Google Scholar 

  55. Murphy Michael P (2009) How mitochondria produce reactive oxygen species. Biochem J 417(1):1–13. https://doi.org/10.1042/bj20081386

    Article  CAS  PubMed  Google Scholar 

  56. Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11:872–884. https://doi.org/10.1038/nrm3013

    Article  CAS  PubMed  Google Scholar 

  57. Bertram R, Gram Pedersen M, Luciani DS, Sherman A (2006) A simplified model for mitochondrial ATP production. J Theor Biol 243(4):575–586. https://doi.org/10.1016/j.jtbi.2006.07.019

    Article  CAS  PubMed  Google Scholar 

  58. Hatefi Y (1985) The mitochondrial electron transport and oxidative phosphorylation system. Annu Rev Biochem 54(1):1015–1069. https://doi.org/10.1146/annurev.bi.54.070185.005055

    Article  CAS  PubMed  Google Scholar 

  59. Wang K, Yin XM, Chao DT, Milliman CL, Korsmeyer SJ (1996) BID: a novel BH3 domain-only death agonist. Genes Dev 10(22):2859–2869. https://doi.org/10.1101/gad.10.22.2859

    Article  CAS  PubMed  Google Scholar 

  60. Gross A, Yin X-M, Wang K, Wei MC, Jockel J, Milliman C, Erdjument-Bromage H, Tempst P et al (1999) Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J Biol Chem 274(2):1156–1163. https://doi.org/10.1074/jbc.274.2.1156

    Article  CAS  PubMed  Google Scholar 

  61. Eskes R, Desagher S, Antonsson B, Martinou J-C (2000) Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol 20(3):929–935. https://doi.org/10.1128/mcb.20.3.929-935.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ (2000) tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 14(16):2060–2071. https://doi.org/10.1101/gad.14.16.2060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Neitemeier S, Jelinek A, Laino V, Hoffmann L, Eisenbach I, Eying R, Ganjam GK, Dolga AM et al (2017) BID links ferroptosis to mitochondrial cell death pathways. Redox Biol 12:558–570. https://doi.org/10.1016/j.redox.2017.03.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Feng H, Stockwell BR (2018) Unsolved mysteries: how does lipid peroxidation cause ferroptosis? PLoS Biol 16(5):e2006203. https://doi.org/10.1371/journal.pbio.2006203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chaudiere J, Wilhelmsen EC, Tappel AL (1984) Mechanism of selenium-glutathione peroxidase and its inhibition by mercaptocarboxylic acids and other mercaptans. J Biol Chem 259(2):1043–1050

    CAS  PubMed  Google Scholar 

  66. Cardoso BR, Hare DJ, Bush AI, Roberts BR (2016) Glutathione peroxidase 4: a new player in neurodegeneration? Mol Psychiatry 22:328–335. https://doi.org/10.1038/mp.2016.196

    Article  CAS  PubMed  Google Scholar 

  67. Brigelius-Flohé R, Maiorino M (2013) Glutathione peroxidases. Biochim Biophys Acta Gen Subj 1830(5):3289–3303. https://doi.org/10.1016/j.bbagen.2012.11.020

    Article  CAS  Google Scholar 

  68. Casañas-Sánchez V, Pérez JA, Fabelo N, Herrera-Herrera AV, Fernández C, Marín R, González-Montelongo MC, Díaz M (2014) Addition of docosahexaenoic acid, but not arachidonic acid, activates glutathione and thioredoxin antioxidant systems in murine hippocampal HT22 cells: potential implications in neuroprotection. J Neurochem 131(4):470–483. https://doi.org/10.1111/jnc.12833

    Article  CAS  PubMed  Google Scholar 

  69. Jelinek A, Heyder L, Daude M, Plessner M, Krippner S, Grosse R, Diederich WE, Culmsee C (2018) Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis. Free Radic Biol Med 117:45–57. https://doi.org/10.1016/j.freeradbiomed.2018.01.019

    Article  CAS  PubMed  Google Scholar 

  70. Thangaraj P (2016) In vitro antioxidant assays. In: Pharmacological assays of plant-based natural products. Springer International Publishing, Cham, pp 57–72. https://doi.org/10.1007/978-3-319-26811-8_9

  71. Pfleger J, He M, Abdellatif M (2015) Mitochondrial complex II is a source of the reserve respiratory capacity that is regulated by metabolic sensors and promotes cell survival. Cell Death Dis 6:e1835. https://doi.org/10.1038/cddis.2015.202 https://www.nature.com/articles/cddis2015202#supplementary-information

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E et al (2008) Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab 8(3):237–248. https://doi.org/10.1016/j.cmet.2008.07.005

    Article  CAS  PubMed  Google Scholar 

  73. Lubos E, Loscalzo J, Handy DE (2011) Glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 15(7):1957–1997. https://doi.org/10.1089/ars.2010.3586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Sies H (1993) Ebselen, a selenoorganic compound as glutathione peroxidase mimic. Free Radic Biol Med 14(3):313–323. https://doi.org/10.1016/0891-5849(93)90028-S

    Article  CAS  PubMed  Google Scholar 

  75. Nogueira CW, Zeni G, Rocha JBT (2004) Organoselenium and organotellurium compounds: toxicology and pharmacology. Chem Rev 104(12):6255–6286. https://doi.org/10.1021/cr0406559

    Article  CAS  PubMed  Google Scholar 

  76. Reich HJ, Hondal RJ (2016) Why nature chose selenium. ACS Chem Biol 11(4):821–841. https://doi.org/10.1021/acschembio.6b00031

    Article  CAS  PubMed  Google Scholar 

  77. Poirier J, Miron J, Picard C, Gormley P, Théroux L, Breitner J, Dea D (2014) Apolipoprotein E and lipid homeostasis in the etiology and treatment of sporadic Alzheimer’s disease. Neurobiol Aging 35:S3–S10. https://doi.org/10.1016/j.neurobiolaging.2014.03.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). We also thank the Academic Exchange Fellowships conceded by CAPES (process 88881.134820/2016-01) and Deutscher Akademischer Austauschdienst (DAAD). We are also grateful to the Laboratório Multiusuário de Estudos em Biologia at the Universidade Federal de Santa Catarina (LAMEB/UFSC) for providing its infrastructure for carrying out biochemical analysis.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, SC, Brazil

    Diones Caeran Bueno, Viviane de Souza, Rafaela Rafognatto Andreguetti, Aline Aita Naime, Mark William Lopes & Marcelo Farina

  2. Institute of Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Diones Caeran Bueno, Partha Narayan Dey, Verena Wüllner & Axel Methner

  3. Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre, RS, Brazil

    Rômulo Faria Santos Canto

  4. Department of Chemistry, Federal University of Santa Catarina, Florianópolis, SC, Brazil

    Flávio Augusto Rocha Barbosa & Antônio Luiz Braga

Authors
  1. Diones Caeran Bueno
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  2. Rômulo Faria Santos Canto
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  3. Viviane de Souza
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  4. Rafaela Rafognatto Andreguetti
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  5. Flávio Augusto Rocha Barbosa
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  6. Aline Aita Naime
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  7. Partha Narayan Dey
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  8. Verena Wüllner
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  9. Mark William Lopes
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  10. Antônio Luiz Braga
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  11. Axel Methner
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  12. Marcelo Farina
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Corresponding authors

Correspondence to Diones Caeran Bueno, Axel Methner or Marcelo Farina.

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Bueno, D.C., Canto, R.F.S., de Souza, V. et al. New Probucol Analogues Inhibit Ferroptosis, Improve Mitochondrial Parameters, and Induce Glutathione Peroxidase in HT22 Cells. Mol Neurobiol 57, 3273–3290 (2020). https://doi.org/10.1007/s12035-020-01956-9

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