Repurposing auranofin for treatment of Experimental Cerebral Toxoplasmosis

Abstract

Purposes

Evaluate the effect of auranofin on the early and late stages of chronic infection with Toxoplasma gondii avirulent ME49 strain.

Methods

Swiss albino mice were orally inoculated with 10 cysts of Toxoplasma gondii, and orally treated with auranofin or septazole in daily doses of 20 mg/kg or 100 mg /kg, respectively, for 30 days. Treatment began either on the same day of infection and mice were sacrificed at the 60th day postinfection or the treatment started after 60 days of infection and mice were sacrificed at the 90th day postinfection.

Results

Auranofin significantly reduced the brain cyst burden and inflammatory reaction at both stages of infection compared to the infected non-treated control. More remarkably, auranofin significant reduced the brain cyst burden in the late stage, while septazole failed. Hydrogen peroxide level was significantly increased in the brain homogenate of mice treated with auranofin only at the early stage of infection. Ultrastructral studies revealed that the anti-Toxoplasma effect of auranofin is achieved by changing the membrane permeability and inducing apoptosis.

Conclusions

Thus, auranofin could be an alternative for the standard treatment regimen of toxoplasmosis and these results are considered another achievement for the drug against parasitic infection. Being a FDA-approved drug, it can be rapidly evaluated in clinical trials.

This is a preview of subscription content, access via your institution.

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

References

  1. 1.

    Mordue DG, Sibley LD (1997) Intracellular fate of vacuoles containing Toxoplasma gondii is determined at the time of formation and depends on the mechanism of entry. J Immunol 159(9):4452–4459

    CAS  PubMed  Google Scholar 

  2. 2.

    Robert-Gangneux F, Murat JB, Fricker-Hidalgo H, Brenier-Pinchart MP, Gangneux JP, Pelloux H (2011) The placenta: a main role in congenital toxoplasmosis? Trends Parasitol 27(12):530–536. https://doi.org/10.1016/j.pt.2011.09.005

    Article  PubMed  Google Scholar 

  3. 3.

    Dubey JP, Lindsay DS, Speer CA (1998) Structures of Toxoplasma gondii tachyzoites, bradyzoites, and sporozoites and biology and development of tissue cysts. Clin Microbiol Rev 11:267–299

    CAS  Article  Google Scholar 

  4. 4.

    Skariah S, McIntyre MK, Mordue DG (2010) Toxoplasma gondii: determinants of tachyzoite to bradyzoite conversion. Parasitol Res 107:253–260

    Article  Google Scholar 

  5. 5.

    Luft BJ, Remington JS (1992) Toxoplasmic encephalitis in AIDS (AIDS commentary). Clin Infect Dis 15:211–222

    CAS  Article  Google Scholar 

  6. 6.

    Pearce BD, Kruszon-Moran D, Jones JL (2012) The relationship between Toxoplasma gondii infection and mood disorders in the third national health and nutrition survey. Biol Psychiatry 72:290–295

    Article  Google Scholar 

  7. 7.

    Fajard HV, D’ávila S, Bastos RR, Cyrino CD, De Lima Detoni M, Garcia JL, Das Neves LB, Nicolau JL, Amendoeira MR (2013) Seroprevalence and risk factors of toxoplasmosis in cattle from extensive and semi-intensive rearing systems at Zona da Mata, Minas Gerais state. Southern Brazil. Parasit Vectors 6:191. https://doi.org/10.1186/1756-3305-6-191

    Article  Google Scholar 

  8. 8.

    Wei HX, Wei SS, Lindsay DS, Peng HJ (2015) A systematic review and meta-analysis of the efficacy of anti-Toxoplasma gondii medicines in humans. PLoS ONE 10:e0138204. https://doi.org/10.1371/journal.pone.0138204

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Reynolds MG, Oh J, Roos DS (2001) In vitro generation of novel pyrimethamine resistance mutations in the Toxoplasma gondii dihydrofolate reductase. Antimicrob Agents Chemother 45:1271–1277

    CAS  Article  Google Scholar 

  10. 10.

    Sordet F, Aumjaud Y, Fessi H, Derouin F (1998) Assessment of the activity of atovaquone-loaded nanocapsules in the treatment of acute and chronic murine toxoplasmosis. Parasite 5(3):223–229

    CAS  Article  Google Scholar 

  11. 11.

    Dike SY, Singh D, Thankachen BN, Sharma B, Mathur PK, Kore S, Kumar AA (2014) Single-pot synthesis of atovaquone: an antiparasitic drug of choice. Org Process Re Dev 18:618–625

    CAS  Article  Google Scholar 

  12. 12.

    Abou-El-Naga IF, El Kerdany ED, Mady RF, Shalaby TI, Zaytoun EM (2017) The effect of lopinavir/ritonavir and lopinavir/ritonavir loaded PLGA nanoparticles on experimental toxoplasmosis. Parasitol Int 66(6):735–747. https://doi.org/10.1016/j.parint.2017.08.007

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Cox AG, Brown KK, Arner ES, Hampton MB (2008) The thioredoxin reductase inhibitor auranofin triggers apoptosis through a Bax/Bak-dependent process that involves peroxiredoxin 3 oxidation. Biochem Pharmacol 76:1097–1109. https://doi.org/10.1016/j.bcp.2008.08.021

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Katz WA, Alexander S, Bland JH, Blechman W, Bluhm GB, Bonebrake RA et al (1982) The efficacy and safety of auranofin compared to placebo in rheumatoid arthritis. J Rheumatol Suppl 8:173–178

    CAS  PubMed  Google Scholar 

  15. 15.

    Madeira JM, Schindler SM, Klegeris AA (2015) New look at auranofin, dextromethorphan and rosiglitazone for reduction of glia-mediated inflammation in neurodegenerative diseases. Neural Regen Res 10(3):391–393. https://doi.org/10.4103/1673-5374.153686

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Abou-El-Naga IF, Gaafar MR, Gomaa MM, Khedr SI, El Achy SN (2019) Encephalitozoon intestinalis: A new target for auranofin in a mice model. Med Mycol. https://doi.org/10.1093/mmy/myz126 (myz126)

    Article  PubMed  Google Scholar 

  17. 17.

    Abou-El-Naga IF, Mady RF, Mogahed NMFH (2020) In vitro effectivity of three approved drugs and their synergistic interaction against Leishmania infantum. Biomédica 40(Supl.1):89–101

    Article  Google Scholar 

  18. 18.

    Debnath A, Ndao M, Reed SL (2013) Reprofiled drug targets ancient protozoans. Gut Microbes 4(1):66–71

    Article  Google Scholar 

  19. 19.

    Peroutka-Bigus N, Bellaire BH (2019) Antiparasitic activity of auranofin against pathogenic Naegleria fowleri. J Eukaryot Microbiol. https://doi.org/10.1111/jeu.12706

    Article  PubMed  Google Scholar 

  20. 20.

    Tejman-Yarden N, Miyamoto Y, Leitsch D, Santini J, Debnath A, Gut J et al (2013) A reprofiled drug, auranofin, is effective against metronidazole-resistant Giardia lamblia. Antimicrob Agents Chemother 57(5):2029–2035. https://doi.org/10.1128/AAC.01675-12

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    da Silva MT, Silva-Jardim I, Portapilla GB, de Lima GM, Costa FC, Anibal FF, Thiemann OH (2016) In vivo and in vitro auranofin activity against Trypanosoma cruzi: Possible new uses for an old drug. Exp Parasitol 166:189–193. https://doi.org/10.1016/j.exppara.2015.05.012

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Sharlow ER, Leimgruber S, MurrayS LA, Sciotti RJ, Hickman M et al (2014) Auranofin is an apoptosis-simulating agent Auranofin with in vitro and in vivo anti-leishmanial activity. ACS Chem Biol 9(3):663–672

    CAS  Article  Google Scholar 

  23. 23.

    Andrade RM, Chaparro JD, Capparelli E, Reed SL (2014) Auranofin is highly efficacious against Toxoplasma gondii in vitro and in an in vivo experimental model of acute toxoplasmosis. PLoS Negl Trop Dis 8(7):e2973. https://doi.org/10.1371/journal.pntd.0002973

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Pessetto ZY, Weir SJ, Sethi G, Broward MA, Godwin AK (2013) Drug repurposing for gastrointestinal stromal tumor. Mol Cancer Ther 12(7):1299–1309. https://doi.org/10.1158/1535-7163.mct-12-0968

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Angelucci F, Sayed AA, Williams DL, Boumis G, Brunori M, Dimastrogiovanni D et al (2009) Inhibition of Schistosoma mansoni thioredoxin-glutathione reductase by auranofin: structural and kinetic aspects. J Biol Chem 284:28977–28985. https://doi.org/10.1074/jbc.M109.020701

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Parsonage D, Sheng F, Hirata K, Debnath A, Mckerrow JH, Reed SL et al (2016) X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action. J Struct Biol 194:180–190. https://doi.org/10.1016/j.jsb.2016.02.015

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Capparelli EV, Bricker-Ford R, Rogers MJ, McKerrow JH, Reed SL (2017) Phase I clinical trial results of auranofin, a novel antiparasitic agent. Antimicrob Agents Chemother 61(1):e01947-e2016. https://doi.org/10.1128/AAC.01947-16

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Gamberi T, Fiaschi T, Modesti A, Massai L, Messori L, Balzi M et al (2015) Evidence that the antiproliferative effects of auranofin in Saccharomyces cerevisiae arise from inhibition of mitochondrial respiration. Int J Biochem Cell Biol 65:61–71. https://doi.org/10.1016/j.biocel.2015.05.016

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Dubey JP, Frenkel JK (1976) Feline toxoplasmosis from acutely infected mice and the development of Toxoplasma cysts. J Protozool 23(4):537–546

    CAS  Article  Google Scholar 

  30. 30.

    Hermes G, Ajioka JW, Kelly KA, Mui E, Roberts F, Kasza K et al (2008) Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neural injury in brains of mice due to common, persistent, parasitic infection. J Neuroinflammation 5:48–85

    Article  Google Scholar 

  31. 31.

    Bottari NB, Baldissera MD, Tonin AA, Rech VC, Nishihira VS, Thomé GR et al (2015) Sulfamethoxazole-trimethoprim associated with resveratrol for the treatment of toxoplasmosis in mice: influence on the activity of enzymes involved in brain neurotransmission. Microb Pathog 79:17–23

    CAS  Article  Google Scholar 

  32. 32.

    El-Zawawy LA, El-Said D, Mossallam SF, Ramadan HS, Younis SS (2015) Preventive prospective of triclosan and triclosan-liposomal nanoparticles against experimental infection with a cystogenic ME49 strain of Toxoplasma gondii. Acta Trop 141(Pt A):103–111. https://doi.org/10.1016/j.actatropica.2014.09.020

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Eissa MH, Antnious SN, Salama MM, Fikry AA, Morsy TA (1990) Histopathological studies of acute, chronic and congenital infection of toxoplasmosis in mice. J Egy Soc Parasitol 20(2):805–816

    CAS  Google Scholar 

  34. 34.

    Marzano C, Gandin V, Folda A, Scutari G, Bindoli A, Rigobello MP (2007) Inhibition of thioredoxin reductase by auranofin induces apoptosis in cisplatin-resistant human ovarian cancer cells. Free Radic Biol Med 42(6):872–881

    CAS  Article  Google Scholar 

  35. 35.

    Sun D, Crowell SA, Harding CM, De Silva PM, Harrison A, Fernando DM et al (2016) KatG and KatE confer Acinetobacter resistance to hydrogen peroxide but sensitize bacteria to killing by phagocytic respiratory burst. Life Sci 148:31–40. https://doi.org/10.1016/j.lfs.2016.02.015

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Hayat MA (2000) Principles and techniques of electron microscopy: biological applications. VNR Company, New York, USA

    Google Scholar 

  37. 37.

    Kirkpatrick LA, Feeney BC (2013) A simple guide to IBM SPSS statistics for version 20.0. Student ed. Belmont, Calif. Wadsworth, Cengage Learning 115

  38. 38.

    Innes EA (2010) Vaccination against Toxoplasma gondii: an increasing priority for collaborative research? Expert Rev Vaccines 9(10):1117–1119. https://doi.org/10.1586/erv.10.113

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Chew WK, Wah MJ, Ambu S, Segarra I (2012) Toxoplasma gondii: determination of the onset of chronic infection in mice and the in vitro reactivation of brain cysts. Exp Parasitol 130:22–25

    Article  Google Scholar 

  40. 40.

    Djurković-Djaković O, Milenković V, NikolićBobić AB, Grujić J (2002) Efficacy of atovaquone combined with clindamycin against murine infection with a cystogenic (Me49) strain of Toxoplasma gondii. JAntimicrob Chemother 50(6):981–987

    Article  Google Scholar 

  41. 41.

    Israelski DM, Remington JS (1993) Toxoplasma gondii is an intracellular protozoan parasite: toxoplasmosis in the non-AIDS immunocompromised host. Curr Clin Top Infect 13:322–356

    CAS  Google Scholar 

  42. 42.

    Faucher B, Moreau J, Zaegel O, Frank J, Piarroux P (2011) Failure of conventional treatment with pyrimethamine and sulfadiazine for secondary prophylaxis of cerebral toxoplasmosis in a patient with AIDS. J Antimicrob Chemother 66:1654–1656

    CAS  Article  Google Scholar 

  43. 43.

    Carruthers VB, Suzuki Y (2007) Effects of Toxoplasma gondii infection on the brain. Schizophr Bull 33:745–751

    Article  Google Scholar 

  44. 44.

    AraujoFG H-M, Gutteridge WE, Remington JS (1992) In vitro and in vivo activities of the hydroxynaphthoquinone 566C80 against the cyst form of Toxoplasma gondii. Antimicrob Agents Chemother 36(2):326–330

    Article  Google Scholar 

  45. 45.

    Costa IN, Angeloni MB, Santana LA, Barbosa BF, Silva MC, Rodrigues AA et al (2009) Azithromycin inhibits vertical transmission of Toxoplasma gondii in Calomys callosus (Rodentia: Cricetidae). Placenta 30(10):884–890. https://doi.org/10.1016/j.placenta.2009.08.002

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Xue J, Jiang W, Chen Y, Gong F, Wang M, Zeng P et al (2017) Thioredoxin reductase from Toxoplasma gondii: an essential virulence effector with antioxidant function. FASEB J 31(10):4447–4457. https://doi.org/10.1096/fj.201700008R

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Carvalho AP, Fernandes PA, Ramos MJ (2006) Similarities and differences in the thioredoxin superfamily. Prog Biophys Mol Biol 91:229–248

    CAS  Article  Google Scholar 

  48. 48.

    Stewart EJ, Aslund F, Beckwith J (1998) Disulfide bond formation in the Escherichia coli cytoplasm: an in vivo role reversal for the thioredoxins. EMBO J 17:5543–5550. https://doi.org/10.1093/emboj/17.19.5543

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Harbut MB, Vilchèze C, Luo X, Hensler ME, Guo H, Yang B et al (2015) Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis. Proc Natl Acad Sci USA 112:4453–4458. https://doi.org/10.1073/pnas.1504022112

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Madeira JM, Gibson DL, Kean WF, Klegeris A (2012) The biological activity of auranofin: implications for novel treatment of diseases. Inflammopharmacology 20:297–306. https://doi.org/10.1007/s10787-012-0149-1

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Madeira JM, Renschler CJ, Mueller B, Hashioka S, Gibson DL, Klegeris A (2013) Novel protective properties of auranofn: inhibition of human astrocyte cytotoxic secretions and direct neuroprotection. Life Sci 92:1072–1080. https://doi.org/10.1016/j.lfs.2013.04.005

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Madeira JM, Bajwa E, Stuart MJ, Hashioka S, Klegeris A (2014) Gold drug auranofn could reduce neuroinflammation by inhibiting microglia cytotoxic secretions and primed respiratory burst. J Neuroimmunol 276:71–79

    CAS  Article  Google Scholar 

  53. 53.

    Hammouda NA, Rashwan EA, Hussien ED, Abo el-Naga I, Fathy FM (1995) Measurement of respiratory burst of TNF and IL-1 cytokine activated murine peritoneal macrophages challenged with Toxoplasma gondii. J Egypt Soc Parasitol 25(3):683–691

    CAS  PubMed  Google Scholar 

  54. 54.

    Engin AB, Dogruman-Al F, Ercin U, Celebi B, Babur C, Bukan N (2012) Oxidative stress and tryptophan degradation pattern of acute Toxoplasma gondii infection in mice. Parasitol Res 111:1725–1730

    Article  Google Scholar 

  55. 55.

    Gais A, Beinert N, Gross U, Lüder CG (2008) Transient inhibition of poly (ADP-ribose) polymerase expression and activity by Toxoplasma gondii is dispensable for parasite-mediated blockade of host cell apoptosis and intracellular parasite replication. Microbes Infect 10(4):358–366. https://doi.org/10.1016/j.micinf.2007.12.010

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    De Rocher AE, Coppens I, Karnataki A, Gilbert LA, Rome ME, Feagin JE et al (2008) A thioredoxin family protein of the apicoplast periphery identifies abundant candidate transport vesicles in Toxoplasma gondii. Eukaryot Cell 7(9):1518–1529. https://doi.org/10.1128/EC.00081-08

    CAS  Article  Google Scholar 

  57. 57.

    Gajria B, Bahl A, Brestelli J, Dommer J, Fischer S, Gao X et al (2008) ToxoDB: an integrated Toxoplasma gondii database resource. Nucleic Acids Res 36:D553-556

    CAS  Article  Google Scholar 

  58. 58.

    Portes JA, Souza TG, dos Santos TA, da Silva LL, RibeiroTP PMD et al (2015) Reduction of toxoplasma gondii development due to inhibition of parasite antioxidant enzymes by a dinuclear iron(III) compound. Antimicrob Agents Chemother 59(12):7374–7386. https://doi.org/10.1128/AAC.00057-15

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Moncada D, Arenas A, Acosta A, Molina D, Hernandez A, Cardona N et al (2016) Role of the 52 KDa thioredoxin protein disulfide isomerase of Toxoplasma gondii during infection to human cells. Exp Parasitol 164:36–42

    CAS  Article  Google Scholar 

  60. 60.

    Rigobello MP, Scutari G, Boscolo R, Bindoli A (2002) Induction of mitochondrial permeability transition by auranofin, a gold (I)-phosphine derivative. Br J Pharmacol 136:1162–1168

    CAS  Article  Google Scholar 

  61. 61.

    Ilari A, Baiocco P, Messori L, Fiorillo A, Boffi A, Gramiccia M et al (2012) A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantumin complex with auranofin reveals a dual mechanism of enzyme inhibition. Amino Acids 42(2–3):803–811

    CAS  Article  Google Scholar 

  62. 62.

    Chircorian A, Barrios AM (2004) Inhibition of lysosomal cysteine proteases by chrysotherapeutic compounds: a possible mechanism for the antiarthritic activity of Au (I). Bioorg Med Chem Lett 14(20):5113–5116

    CAS  Article  Google Scholar 

  63. 63.

    Krishnamurthy D, Karver MR, Fiorillo E, Orrú V, Stanford SM, Bottini N, Barrios AM (2008) Gold(I)-mediated inhibition of protein tyrosine phosphatases: a detailed in vitro and cellular study. J Med Chem 51(15):4790–4795. https://doi.org/10.1021/jm800101w

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

Dr Ashraf Barakat, Professor of Epidemiology and Zoonotic Diseases, National Research Centre, Dokii, Giza, Egypt for providing us with Me49 strain.

Funding

None.

Author information

Affiliations

Authors

Contributions

All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Nermine Mogahed Fawzy Hussein Mogahed.

Ethics declarations

Conflict of Interest

The authors declared that they have 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

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Abou-El-Naga, I.F., Mogahed, N.M.F.H. Repurposing auranofin for treatment of Experimental Cerebral Toxoplasmosis. Acta Parasit. (2021). https://doi.org/10.1007/s11686-021-00337-z

Download citation

Keywords

  • Auranofin
  • Cerebral toxoplasmosis
  • Me49
  • Toxoplasma cyst