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Design, Synthesis, and In Vitro Evaluation of a Novel Probucol Derivative: Protective Activity in Neuronal Cells Through GPx Upregulation

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Abstract

Recent studies have shown that probucol (PB), a hipocholesterolemic agent with antioxidant and anti-inflammatory properties, presents neuroprotective properties. On the other hand, adverse effects have limited PB’s clinical application. Thus, the search for PB derivatives with no or less adverse effects has been a topic of research. In this study, we present a novel organoselenium PB derivative (RC513) and investigate its potential protective activity in an in vitro experimental model of oxidative toxicity induced by tert-butyl hydroperoxide (tBuOOH) in HT22 neuronal cells, as well as exploit potential protective mechanisms. tBuOOH exposure caused a significant decrease in the cell viability, which was preceded by (i) increased reactive species generation and (ii) decreased mitochondrial maximum oxygen consumption rate. RC513 pretreatment (48 h) significantly prevented the tBuOOH-induced decrease of cell viability, RS generation, and mitochondrial dysfunction. Of note, RC513 significantly increased glutathione peroxidase (GPx) activity and mRNA expression of GPx1, a key enzyme involved in peroxide detoxification. The use of mercaptosuccinic acid, an inhibitor of GPx, significantly decreased the protective activity of RC513 against tBuOOH-induced cytotoxicity in HT22 cells, highlighting the importance of GPx upregulation in the observed protection. In summary, the results showed a significant protective activity of a novel PB derivative against tBuOOH-induced oxidative stress and mitochondrial dysfunction, which was related to the upregulation of GPx. Our results point to RC513 as a promising neuroprotective molecule, even though studies concerning potential beneficial effects and safety aspects of RC513 under in vivo conditions are well warranted.

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Abbreviations

PB:

Probucol

GPx:

Glutathione peroxidase

SH:

Glutathione

GR:

Glutathione reductase

NADPH:

β-Nicotinamide adenine dinucleotide phosphate sodium salt reduced

DMSO:

Dimethyl sulfoxide

MTT:

3-(4,5-Dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide

PI:

Propidium iodide

DCFH2-DA:

2′,7′-Dichlorofluorescein diacetate

tBuOOH:

tert-Butyl hydroperoxide

MS:

Mercaptosuccinic acid

DTNB:

5,5′-Dithiobis(2-nitrobenzoic acid)

FCCP:

Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

HBSS:

Hank’s balanced salt solution

NPSH:

Non-protein thiols

References

  1. Sies H, Jones D (2007) Oxidative stress. Encycl Stress:45–48

  2. Sies H (2015) Oxidative stress: a concept in redox biology and medicine. Redox Biol 4:180–183. https://doi.org/10.1016/j.redox.2015.01.002

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Bozzo F, Mirra A, Carrì MT (2017) Oxidative stress and mitochondrial damage in the pathogenesis of ALS: new perspectives. Neurosci Lett 636:3–8. https://doi.org/10.1016/j.neulet.2016.04.065

    Article  PubMed  CAS  Google Scholar 

  4. Ganguly G, Chakrabarti S, Chatterjee U, Saso L (2017) Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer’s disease and Parkinson’s disease. Drug Des Devel Ther 11:797–810. https://doi.org/10.2147/DDDT.S130514

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Liu Z, Zhou T, Ziegler AC et al (2017) Oxidative stress in neurodegenerative diseases: from molecular mechanisms to clinical applications. Oxidative Med Cell Longev 2017:1–11

    Google Scholar 

  6. Jin H, Kanthasamy A, Ghosh A, Anantharam V, Kalyanaraman B, Kanthasamy AG (2014) Mitochondria-targeted antioxidants for treatment of Parkinson’s disease: preclinical and clinical outcomes. Biochim Biophys Acta Mol Basis Dis 1842(8):1282–1294. https://doi.org/10.1016/j.bbadis.2013.09.007

    Article  CAS  Google Scholar 

  7. Sandhir R, Yadav A, Sunkaria A, Singhal N (2015) Nano-antioxidants: an emerging strategy for intervention against neurodegenerative conditions. Neurochem Int 89:209–226. https://doi.org/10.1016/j.neuint.2015.08.011

    Article  PubMed  CAS  Google Scholar 

  8. Ruan Q, Ruan J, Zhang W, Qian F, Yu Z (2017) Targeting NAD+ degradation: the therapeutic potential of flavonoids for Alzheimer’s disease and cognitive frailty. Pharmacol Res. https://doi.org/10.1016/j.phrs.2017.08.010

  9. Yamashita S, Hbujo H, Arai H et al (2008) Long-term probucol treatment prevents secondary cardiovascular events: a cohort study of patients with heterozygous familial hypercholesterolemia in Japan. J Atheroscler Thromb 15(6):292–303. https://doi.org/10.5551/jat.E610

    Article  PubMed  Google Scholar 

  10. Santos DB, Peres KC, Ribeiro RP, Colle D, Santos AA, Moreira ELG, Souza DOG, 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  PubMed  CAS  Google Scholar 

  11. Colle D, Santos DB, Moreira ELG et al (2013) Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats. PLoS One 8:1–15

    Article  Google Scholar 

  12. 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  PubMed  CAS  Google Scholar 

  13. 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  PubMed  CAS  Google Scholar 

  14. Colle D, Santos DB, Hartwig JM, Godoi M, Braga AL, Farina M (2013) Mitochondrion succinobucol versus probucol : higher efficiency of succinobucol in mitigating 3-NP-induced brain mitochondrial dysfunction and oxidative stress in vitro. Mitochondrion 13(2):125–133. https://doi.org/10.1016/j.mito.2013.01.005

    Article  PubMed  CAS  Google Scholar 

  15. Tardif J-C, Gregoire J, L’Allier PL (2002) Prevention of restenosis with antioxidants: mechanisms and implications. Am J Cardiovasc Drugs 2(5):323–334. https://doi.org/10.2165/00129784-200202050-00005

    Article  PubMed  CAS  Google Scholar 

  16. McDowell I, Brennan G, McEneny J et al (1994) The effect of probucol and vitamin E treatment on the oxidation of low-density lipoprotein and forearm vascular responses in humans. Eur J Clin Investig 24(11):759–765. https://doi.org/10.1111/j.1365-2362.1994.tb01073.x

    Article  CAS  Google Scholar 

  17. Tardif JC, 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  PubMed  CAS  Google Scholar 

  18. 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  PubMed  CAS  Google Scholar 

  19. Nogueira CW, Zeni G, Rocha JBT (2004) Organoselenium and organotellurium compounds: toxicology and pharmacology. Chem Rev 104(12):6255–6285. https://doi.org/10.1021/cr0406559

    Article  PubMed  CAS  Google Scholar 

  20. Posser T, Franco JL, dos Santos DA, Rigon AP, Farina M, Dafré AL, Teixeira Rocha JB, Leal RB (2008) Diphenyl diselenide confers neuroprotection against hydrogen peroxide toxicity in hippocampal slices. Brain Res 1199:138–147. https://doi.org/10.1016/j.brainres.2008.01.004

    Article  PubMed  CAS  Google Scholar 

  21. Dobrachinski F, da Silva MH, Tassi CLC, de Carvalho NR, Dias GRM, Golombieski RM, da Silva Loreto ÉL, da Rocha JBT et al (2014) Neuroprotective effect of diphenyl diselenide in a experimental stroke model: maintenance of redox system in mitochondria of brain regions. Neurotox Res 26(4):317–330. https://doi.org/10.1007/s12640-014-9463-2

    Article  PubMed  CAS  Google Scholar 

  22. Rosa RM, Flores DG, Appelt HR, Braga AL, Henriques JAP, Roesler R (2003) Facilitation of long-term object recognition memory by pretraining administration of diphenyl diselenide in mice. Neurosci Lett 341(3):217–220. https://doi.org/10.1016/S0304-3940(03)00187-3

    Article  PubMed  CAS  Google Scholar 

  23. Stangherlin EC, Luchese C, Pinton S, Rocha JBT, Nogueira CW (2008) Sub-chronical exposure to diphenyl diselenide enhances acquisition and retention of spatial memory in rats. Brain Res 1201:106–113. https://doi.org/10.1016/j.brainres.2008.01.061

    Article  PubMed  CAS  Google Scholar 

  24. Pinton S, da Rocha JT, Zeni G, Nogueira CW (2010) Organoselenium improves memory decline in mice: involvement of acetylcholinesterase activity. Neurosci Lett 472(1):56–60. https://doi.org/10.1016/j.neulet.2010.01.057

    Article  PubMed  CAS  Google Scholar 

  25. Pinton S, Trevisan J, Gai BM, Prigol M (2011) Neuroprotector effect of p,p’-methoxyl- diphenyl diselenide in a model of sporadic dementia of Alzheimer’s type in mice: contribution of antioxidant mechanism. Cell Biochem Funct 29(3):235–243. https://doi.org/10.1002/cbf.1741

    Article  PubMed  CAS  Google Scholar 

  26. Pinton S, Souza AC, Sari MHM, Ramalho RM, Rodrigues CMP, Nogueira CW (2013) P,p’-Methoxyl-diphenyl diselenide protects against amyloid-β induced cytotoxicity in vitro and improves memory deficits in vivo. Behav Brain Res 247:241–247. https://doi.org/10.1016/j.bbr.2013.03.034

    Article  PubMed  CAS  Google Scholar 

  27. Pinton S, Brüning CA, Sartori Oliveira CE, Prigol M, Nogueira CW (2013) Therapeutic effect of organoselenium dietary supplementation in a sporadic dementia of Alzheimer’s type model in rats. J Nutr Biochem 24(1):311–317. https://doi.org/10.1016/j.jnutbio.2012.06.012

    Article  PubMed  CAS  Google Scholar 

  28. Barbosa NV, Nogueira CW, Nogara PA, de Bem AF, Aschner M, Rocha JBT (2017) Organoselenium compounds as mimics of selenoproteins and thiol modifier agents. Metallomics 9(12):1703–1734. https://doi.org/10.1039/C7MT00083A

    Article  PubMed  CAS  Google Scholar 

  29. Fiuza B, Subelzú N, Calcerrada P, Straliotto MR, Piacenza L, Cassina A, Rocha JBT, Radi R et al (2015) Impact of SIN-1-derived peroxynitrite flux on endothelial cell redox homeostasis and bioenergetics: protective role of diphenyl diselenide via induction of peroxiredoxins. Free Radic Res 49(2):122–132. https://doi.org/10.3109/10715762.2014.983096

    Article  PubMed  CAS  Google Scholar 

  30. de Bem AF, Fiuza B, Calcerrada P et al (2013) Protective effect of diphenyl diselenide against peroxynitrite-mediated endothelial cell death: a comparison with ebselen. Nitric Oxide 31:20–30

    Article  PubMed  Google Scholar 

  31. 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  PubMed  CAS  Google Scholar 

  32. Liu J, Li L, Suo WZ (2009) HT22 hippocampal neuronal cell line possesses functional cholinergic properties. Life Sci 84(9-10):267–271. https://doi.org/10.1016/j.lfs.2008.12.008

    Article  PubMed  CAS  Google Scholar 

  33. Poteet E, Winters A, Yan LJ, Shufelt K, Green KN, Simpkins JW, Wen Y, Yang SH (2012) Neuroprotective actions of methylene blue and its derivatives. PLoS One 7(10):e48279. https://doi.org/10.1371/journal.pone.0048279

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Jirásek P, Amslinger S, Heilmann J (2014) Synthesis of natural and non-natural curcuminoids and their neuroprotective activity against glutamate-induced oxidative stress in HT-22 cells. J Nat Prod 77(10):2206–2217. https://doi.org/10.1021/np500396y

    Article  PubMed  CAS  Google Scholar 

  35. Lee DS, Cha BY, Woo JT, Kim YC, Jang JH (2015) Acerogenin A from Acer nikoense maxim prevents oxidative stress-induced neuronal cell death through Nrf2-mediated heme oxygenase-1 expression in mouse hippocampal HT22 cell line. Molecules 20(7):12545–12557. https://doi.org/10.3390/molecules200712545

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. 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  PubMed  CAS  Google Scholar 

  37. 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  PubMed  PubMed Central  CAS  Google Scholar 

  38. Salvi A, Patki G, Khan E, Asghar M, Salim S (2016) Protective effect of tempol on buthionine sulfoximine-induced mitochondrial impairment in hippocampal derived HT22 cells. Oxidative Med Cell Longev 2016:1–8. https://doi.org/10.1155/2016/5059043

    Article  CAS  Google Scholar 

  39. Amoroso S, Gioielli A, Cataldi M, di Renzo G, Annunziato L (1999) In the neuronal cell line SH-SY5Y, oxidative stress-induced free radical overproduction causes cell death without any participation of intracellular Ca2+ increase. Biochim Biophys Acta Mol Cell Res 1452(2):151–160. https://doi.org/10.1016/S0167-4889(99)00110-X

    Article  CAS  Google Scholar 

  40. Bae SJ, Lee JS, Kim JM, Lee EK, Han YK, Kim HJ, Choi J, Ha YM et al (2010) 5-Hydroxytrytophan inhibits tert-butylhydroperoxide (t-BHP)-induced oxidative damage via the suppression of reactive species (RS) and nuclear factor-kappaB (NF-kappaB) activation on human fibroblast. J Agric Food Chem 58(10):6387–6394. https://doi.org/10.1021/jf904201h

    Article  PubMed  CAS  Google Scholar 

  41. Kučera O, Endlicher R, Roušar T, Lotková H, Garnol T, Drahota Z, Červinková Z (2014) The effect of tert-butyl hydroperoxide-induced oxidative stress on lean and steatotic rat hepatocytes in vitro. Oxidative Med Cell Longev 2014:1–12. https://doi.org/10.1155/2014/752506

    Article  CAS  Google Scholar 

  42. Kang T-H, Baek H-Y, Kim Y-C (2005) Protective effect of jakyak-gamcho-tang extract and its constituents against t-BHP-induced oxidative damage in HT22 cells. Am J Chin Med 33(02):181–189. https://doi.org/10.1142/S0192415X05002850

    Article  PubMed  Google Scholar 

  43. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1-2):55–63. https://doi.org/10.1016/0022-1759(83)90303-4

    Article  PubMed  CAS  Google Scholar 

  44. Riccardi C, Nicoletti I (2006) Analysis of apoptosis by propidium iodide staining and flow cytometry. Nat Protoc 1(3):1458–1461. https://doi.org/10.1038/nprot.2006.238

    Article  PubMed  CAS  Google Scholar 

  45. Brand-Williams W, Cuvelier ME, Berset C (1995) Use of a free radical method to evaluate antioxidant activity. LWT Food Sci Technol 28(1):25–30. https://doi.org/10.1016/S0023-6438(95)80008-5

    Article  CAS  Google Scholar 

  46. Wendel A (1981) Glutathione peroxidase. Methods Enzymol 77:325–333. https://doi.org/10.1016/S0076-6879(81)77046-0

    Article  PubMed  CAS  Google Scholar 

  47. 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  49. 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  PubMed  CAS  Google Scholar 

  50. Kwon MS, Woo SK, Kurland DB, Yoon S, Palmer A, Banerjee U, Iqbal S, Ivanova S et al (2015) Methemoglobin is an endogenous Toll-like receptor 4 ligand-relevance to subarachnoid hemorrhage. Int J Mol Sci 16(3):5028–5046. https://doi.org/10.3390/ijms16035028

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262

    Article  PubMed  CAS  Google Scholar 

  52. Borchert A, Chi CW, Ufer C et al (2006) The role of phospholipid hydroperoxide glutathione peroxidase isoforms in murine embryogenesis. J Biol Chem 281(28):19655–19664. https://doi.org/10.1074/jbc.M601195200

    Article  PubMed  CAS  Google Scholar 

  53. Bansal Y, Silakari O (2014) Multifunctional compounds: smart molecules for multifactorial diseases. Eur J Med Chem 76:31–42. https://doi.org/10.1016/j.ejmech.2014.01.060

    Article  PubMed  CAS  Google Scholar 

  54. Dias KST, Viegas C Jr (2014) Multi-target directed drugs: a modern approach for design of new drugs for the treatment of Alzheimer’s disease. Curr Neuropharmacol 12(3):239–255. https://doi.org/10.2174/1570159X1203140511153200

    Article  PubMed  PubMed Central  Google Scholar 

  55. Kachanov AV, Slabko OY, Baranova OV, Shilova EV, Kaminskii VA (2004) Triselenium dicyanide from malononitrile and selenium dioxide. One-pot synthesis of selenocyanates. Tetrahedron Lett 45(23):4461–4463. https://doi.org/10.1016/j.tetlet.2004.04.071

    Article  CAS  Google Scholar 

  56. Krief A, Delmotte C, Dumont W (1997) Chemoselective reduction of organoselenocyanates to diselenides. Tetrahedron Lett 38(17):3079–3080. https://doi.org/10.1016/S0040-4039(97)00549-2

    Article  CAS  Google Scholar 

  57. Taffess BG, Takahashin N, Kenslersii W, Masonn RP (1987) Generation of free radicals from organic hydroperoxide tumor promoters in isolated mouse keratinocytes. J Biol Chem 262:12143–12149

    Google Scholar 

  58. Toppo S, Flohé L, Ursini F, Vanin S, Maiorino M (2009) Catalytic mechanisms and specificities of glutathione peroxidases: variations of a basic scheme. Biochim Biophys Acta Gen Subj 1790(11):1486–1500. https://doi.org/10.1016/j.bbagen.2009.04.007

    Article  CAS  Google Scholar 

  59. DeLucia AJ, Mustafa MG, Hussain MZ, Cross CE (1975) Ozone interaction with rodent lung. III. Oxidation of reduced glutathione and formation of mixed disulfides between protein and nonprotein sulfhydryls. J Clin Invest 55(4):794–802. https://doi.org/10.1172/JCI107990

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787–795. https://doi.org/10.1038/nature05292

    Article  PubMed  CAS  Google Scholar 

  61. Haidara K, Morel I, Abaléa V, Gascon Barré M, Denizeau F (2002) Mechanism of tert-butylhydroperoxide induced apoptosis in rat hepatocytes: involvement of mitochondria and endoplasmic reticulum. Biochim Biophys Acta Mol Cell Res 1542(1-3):173–185. https://doi.org/10.1016/S0167-4889(01)00178-1

    Article  CAS  Google Scholar 

  62. Piret JP, Arnould T, Fuks B, Chatelain P, Remacle J, Michiels C (2004) Mitochondria permeability transition-dependent tert-butyl hydroperoxide-induced apoptosis in hepatoma HepG2 cells. Biochem Pharmacol 67(4):611–620. https://doi.org/10.1016/j.bcp.2003.09.026

    Article  PubMed  CAS  Google Scholar 

  63. Lv H, Liu Q, Zhou J, Tan G, Deng X, Ci X (2017) Daphnetin-mediated Nrf2 antioxidant signaling pathways ameliorate tert-butyl hydroperoxide (t-BHP)-induced mitochondrial dysfunction and cell death. Free Radic Biol Med 106:38–52. https://doi.org/10.1016/j.freeradbiomed.2017.02.016

    Article  PubMed  CAS  Google Scholar 

  64. Sonee M, Martens JR, Evers MR, Mukherjee SK (2003) The effect of tertiary butylhydroperoxide and nicotinamide on human cortical neurons. Neurotoxicology 24(3):443–448. https://doi.org/10.1016/S0161-813X(03)00019-6

    Article  PubMed  CAS  Google Scholar 

  65. Isonaka R, Hiruma H, Kawakami T (2011) Inhibition of axonal transport caused by tert-butyl hydroperoxide in cultured mouse dorsal root ganglion neurons. J Mol Neurosci 45(2):194–201. https://doi.org/10.1007/s12031-010-9457-3

    Article  PubMed  CAS  Google Scholar 

  66. Hajieva P, Bayatti N, Granold M, Behl C, Moosmann B (2015) Membrane protein oxidation determines neuronal degeneration. J Neurochem 133(3):352–367. https://doi.org/10.1111/jnc.12987

    Article  PubMed  CAS  Google Scholar 

  67. 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  PubMed  CAS  Google Scholar 

  68. 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  PubMed  CAS  Google Scholar 

  69. Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417(1):1–13. https://doi.org/10.1042/BJ20081386

    Article  PubMed  CAS  Google Scholar 

  70. Bolaños JP, Almeida A, Moncada S (2010) Glycolysis: a bioenergetic or a survival pathway? Trends Biochem Sci 35(3):145–149. https://doi.org/10.1016/j.tibs.2009.10.006

    Article  PubMed  CAS  Google Scholar 

  71. Perron NR, Beeson C, Rohrer B (2013) Early alterations in mitochondrial reserve capacity; a means to predict subsequent photoreceptor cell death. J Bioenerg Biomembr 45(1-2):101–109. https://doi.org/10.1007/s10863-012-9477-5

    Article  PubMed  CAS  Google Scholar 

  72. Lyakhovich A, Graifer D (2015) Mitochondria-mediated oxidative stress: old target for new drugs. Curr Med Chem 22(26):3040–3053. https://doi.org/10.2174/0929867322666150729114036

    Article  PubMed  CAS  Google Scholar 

  73. Ursini F, Maiorino M, Brigelius-Flohé R et al (1995) Diversity of glutathione peroxidases. Methods Enzymol 252:38–53

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  75. Edmunds RC, McIntyre JK, Adam Luckenbach J et al (2014) Toward enhanced MIQE compliance: reference residual normalization of qPCR gene expression data. J Biomol Tech 25(2):54–60. https://doi.org/10.7171/jbt.14-2502-003

    Article  PubMed  PubMed Central  Google Scholar 

  76. 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

    PubMed  CAS  Google Scholar 

  77. Dunning S, ur Rehman A, Tiebosch MH, Hannivoort RA, Haijer FW, Woudenberg J, van den Heuvel FAJ, Buist-Homan M et al (2013) Glutathione and antioxidant enzymes serve complementary roles in protecting activated hepatic stellate cells against hydrogen peroxide-induced cell death. Biochim Biophys Acta Mol Basis Dis 1832(12):2027–2034. https://doi.org/10.1016/j.bbadis.2013.07.008

    Article  CAS  Google Scholar 

  78. Adams WJJ, Kocsis JJ, Snyder R (1989) Acute toxicity and urinary excretion of diphenyldiselenide. Toxicol Lett 48(3):301–310. https://doi.org/10.1016/0378-4274(89)90057-X

    Article  PubMed  CAS  Google Scholar 

  79. Schwarz K, Foltz C (1958) Factor 3 activity of selenium compounds. J Biol Chem 233(1):245–251

    PubMed  CAS  Google Scholar 

  80. Rocha JBT, Piccoli BC, Oliveira CS (2017) Biological and chemical interest in selenium: a brief historical account. ARKIVOC:457–491

  81. Grossmann A, Wendel A (1983) Non-reactivity of the selenoenzyme glutathione peroxidase with enzymatically hydroperoxidized phospholipids. Eur J Biochem 135(3):549–552. https://doi.org/10.1111/j.1432-1033.1983.tb07687.x

    Article  PubMed  CAS  Google Scholar 

  82. Maiorino M, Gregolin C, Ursini FBT-M in E (1990) [47] Phospholipid hydroperoxide glutathione peroxidase. In: Sies H, Glazer A (eds) Oxygen radicals in biological systems part B: oxygen radicals and antioxidants, 1st edition. Academic Press, pp 448–457

  83. Kriska T, Levchenko VV, Chu FF, Esworthy RS, Girotti AW (2008) Novel enrichment of tumor cell transfectants expressing high levels of type 4 glutathione peroxidase using 7alpha-hydroperoxycholesterol as a selection agent. Free Radic Biol Med 45(5):700–707. https://doi.org/10.1016/j.freeradbiomed.2008.05.022

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The financial support by (i) Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC), (ii) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and (iii) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) is gratefully acknowledged. MF, AFB, and ALB are CNPq fellowship recipients. Part of the work was performed with the support from LAMEB (Laboratório Multiusuário de Ciências Biológicas—UFSC), whose technicians are gratefully acknowledged. The authors are also thankful to CEBIME-UFSC for mass analyses.

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Authors and Affiliations

  1. Programa de Pós-Graduação em Neurociências, Universidade Federal de Santa Catarina, Campus Universitário, Florianópolis, SC, Brazil

    Ruth Liliám Quispe & Marcelo Farina

  2. Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Bloco C, CEP, Florianópolis, Santa Catarina, Brazil

    Ruth Liliám Quispe, Andreza Fabro de Bem & Marcelo Farina

  3. Departamento de Farmacociências, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil

    Rômulo Faria Santos Canto

  4. Departamento de Biologia Celular, Embriologia e Genética, Universidade Federal de Santa Catarina, Campus Universitário, Florianópolis, SC, Brazil

    Michael Lorenz Jaramillo

  5. Departamento de Química, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil

    Flavio Augusto Rocha Barbosa & Antônio Luiz Braga

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  1. Ruth Liliám Quispe
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  2. Rômulo Faria Santos Canto
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  3. Michael Lorenz Jaramillo
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  4. Flavio Augusto Rocha Barbosa
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  5. Antônio Luiz Braga
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  6. Andreza Fabro de Bem
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  7. Marcelo Farina
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Correspondence to Ruth Liliám Quispe or Marcelo Farina.

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Electronic Supplementary Material

Fig. S1

Antioxidant activity of RC513. RC513 (25 μM) or trolox (positive control) were incubated with the stable radical DPPH (500 μM) during 30 min at room temperature. Expressed results as percentage of antioxidant activity. Values are represented as mean ± SEM (n = 3). ** indicates statistical difference (p < 0.01) by Student’s t-test. (GIF 24 kb)

High Resolution Image (TIFF 1849 kb)

Table S1

Temporal expression of Tr2 (thioredoxin reductase 2) gene in RC513-treated HT22 cells. HT22 cells were treated with 2 μM RC513 or vehicle during 3 h, 6 h, 12 h and 24 h. Transcripts levels of Tr2 were normalized with Gapdh gene and calculated by the 2-ΔΔCT method. Values are represented as mean ± SEM (n = 4) (PDF 160 kb)

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Quispe, R.L., Canto, R.F.S., Jaramillo, M.L. et al. Design, Synthesis, and In Vitro Evaluation of a Novel Probucol Derivative: Protective Activity in Neuronal Cells Through GPx Upregulation. Mol Neurobiol 55, 7619–7634 (2018). https://doi.org/10.1007/s12035-018-0939-6

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